Geminal Diheteroatomic Motifs: Some Applications of Acetals, Ketals, and Their Sulfur and Nitrogen Homologues in Medicinal Chemistry and Drug Design
- Yong-Jin Wu*Yong-Jin Wu*Phone: (617) 494-7410. Email: [email protected]Small Molecule Drug Discovery, Bristol Myers Squibb Research and Early Development, 100 Binney Street, Cambridge, Massachusetts 02142, United StatesMore by Yong-Jin Wu and
- Nicholas A. Meanwell*Nicholas A. Meanwell*Phone: (609) 252-6195. Email: [email protected]Department of Discovery and Chemistry and Molecular Technologies, Bristol-Myers Squibb PRI, PO Box 4000, Princeton, New Jersey 08543-4000, United StatesMore by Nicholas A. Meanwell
Copyright © 2021 American Chemical Society
Abstract
Acetals and ketals and their nitrogen and sulfur homologues are often considered to be unconventional and potentially problematic scaffolding elements or pharmacophores for the design of orally bioavailable drugs. This opinion is largely a function of the perception that such motifs might be chemically unstable under the acidic conditions of the stomach and upper gastrointestinal tract. However, even simple acetals and ketals, including acyclic molecules, can be sufficiently robust under acidic conditions to be fashioned into orally bioavailable drugs, and these structural elements are embedded in many effective therapeutic agents. The chemical stability of molecules incorporating geminal diheteroatomic motifs can be modulated by physicochemical design principles that include the judicious deployment of proximal electron-withdrawing substituents and conformational restriction. In this Perspective, we exemplify geminal diheteroatomic motifs that have been utilized in the discovery of orally bioavailable drugs or drug candidates against the backdrop of understanding their potential for chemical lability.
Introduction
ARTICLE SECTIONS
Structural elements in which two heteroatoms, either oxygen, nitrogen, or sulfur or combinations thereof (Figure 1), are bound to a single sp3 carbon atom are often perceived as being problematic scaffolds for the design of drug candidates intended for oral delivery based on an anticipation of instability in the acidic environment of the stomach and the upper gastrointestinal (GI) tract. While this concern may be considered more acute for acyclic derivatives, there are many examples where molecules incorporating geminal diheteroatomic motifs have been gainfully exploited in the design of orally administered drugs and drug candidates, including compounds with acyclic topologies. These motifs find application in situations that take advantage of their specific properties, which can be readily manipulated by the careful selection and deployment of proximal substituents that can confer robust chemical stability under acidic conditions.(1,2) Nevertheless, there are circumstances where geminal diheteroatomic motifs can be labile at low pH or lability can be specifically incorporated by design, with buffered formulations providing a potential drug delivery solution for sensitive molecules that need to be delivered intact by the oral route.(3) However, molecules incorporating diheteroatomic motifs can still be viewed with suspicion as either “unorthodox” or “atypical” functionality to deploy in drug discovery campaigns.(2) Interestingly, Nature relies upon such linkages for the assembly of two of the three major natural polymers, with oligonucleotide concatenation dependent on an N–C–O linkage while the carbohydrate monomers of polysaccharides are connected via O–C–O moieties (Figure 2).(4,5) These bonds offer excellent stability in water at neutral pH with half-lives estimated at between 70 and 230 years for deoxyribonucleic acid (DNA) at 25 °C, of particular importance for information storage, and 20 to 1.2 × 107 years for carbohydrates.(6) Thus, Nature has developed families of enzymes to cleave the N–C–O and O–C–O linkages in nucleotides and carbohydrates.(7,8) A wide range of natural products also incorporate acetal and ketal moieties and their sulfur and nitrogen homologues, with a representative selection of the structures captured by 1–19 in Figure 3.(9) With many of these naturally occurring compounds, biosynthetic accessibility often relies upon inherent chemical reactivity manifolds in which electrophilic species are intercepted in an inter- or intramolecular fashion by an oxygen-, nitrogen- or sulfur-based nucleophile.(9) Despite the view that geminally disposed diheteroatomic motifs might be considered as unconventional vehicles for drug discovery, these structural elements are actually quite prevalent in marketed, orally administered drugs, with a representative selection presented in Figure 4 that collates examples of embedded O–C–O, O–C–N, N–C–N, O–C–S, N–C–S, and S–C–S motifs. Indeed, these motifs have been widely deployed as scaffolds and appendages in a range of circumstances that includes those that demand sufficient stability for oral administration. There are well in excess of 90 drugs currently on the market that incorporate geminal diheteroatomic motifs, with a particular prevalence in therapeutics for infectious diseases where nucleoside analogues and the penicillin and cephem antibiotics are large and prominent classes of N–C–O and N–C–S derivatives, respectively. The inherent stability of geminal diheteroatomic motifs toward hydrolysis or degradation can readily be modulated by judicious compound design that takes advantage of electronic attributes, strain, or steric effects, all of which can be deployed individually or in combination to either stabilize or destabilize a specific functionality toward degradation. The stabilization of geminal diheteroatomic motifs by the incorporation of proximal electron-withdrawing moieties has proven to be a particularly useful approach, with fluorination (F, CF3) perhaps the most common contemporary tactic.(10) However, these motifs can also be specifically exploited to take advantage of chemical instability as part of the engineering of a drug delivery system or a prodrug moiety that depends on a degradation pathway or a self-immolative element.(10c,11) The presence of geminal diheteroatomic motifs in biologically active molecules is not always overtly acknowledged, but the unique properties that are frequently conferred by their application can offer an advantage in problem-solving during candidate optimization. In this Perspective, we provide a synopsis of some of the more prominent and practically useful applications of geminal diheteroatomic motifs in the design of orally bioavailable drugs in a fashion that highlights their attributes while capturing their potential liabilities. Applications of geminal diheteroatomic motifs that are designed as immolating elements in drug delivery or prodrug design will not be discussed.
Figure 1
Figure 1. Structural elements with two heteroatoms, either oxygen, nitrogen, or sulfur or combinations thereof bound to a single sp3 carbon atom that have been exploited in drug design.
Figure 2
Figure 2. Naturally occurring polymers with nucleic acid oligomers and polysaccharides dependent upon geminal diheteroatomic linkages (marked in red), while polypeptides rely upon amide bonds for concatenation.
Figure 3
Figure 3. Select naturally occurring compounds 1–19 that incorporate geminal diheteroatomic motifs, which are marked in red.
Figure 4
Figure 4. Geminal diheteroatomic motifs that are present in marketed oral drugs, which are highlighted in red.
Acetals and Ketals (R–O–C–O–R′)
Despite their natural abundance and the prevalence of successful applications in modern drug discovery, acetals and ketals are still frequently considered to be unconventional structural elements not well-suited for contemporary drug design due to the long-held prejudice that these groups are too labile to survive the acidic environment of the stomach.(1,2) However, as shown by the anticonvulsant topiramate (20), the antiemetic aprepitant (21), and many other marketed drugs, even rather simple ketals and acetals that lack overt stabilizing elements (referred to here as nonstabilized) can be resistant to hydrolytic degradation in the gut.(12,13) Indeed, the dioxolane moiety is embedded in 24 drugs approved by the United States Food and Drug Administration (FDA) prior to 2018, and this ring system was the fifth most prevalent oxygen-containing heterocycle in marketed compounds at that time, a ranking viewed with some surprise.(14) Concerns around chemical stability can be addressed by the judicious introduction of proximal electron-withdrawing groups, basic amines or heteroaryl rings, or the careful implementation of steric and strain effects that can be used to enhance the stability of inherently fragile ketal and acetal derivatives. Compounds incorporating such elements are referred to here as stabilized acetals and ketals. Moreover, the introduction of oxygen atoms into a molecule in the context of an acetal or ketal moiety offers the potential for a favorable H-bonding interaction with a drug target or a productive influence on the conformation of a molecule.(13)
The degradation rate of acetals and ketals is determined by several factors, with the basicity of the oxygen atom and the facility with which it protonates (Scheme 1, step 1) and the stability of the carboxonium (carbonylonium) ion intermediate (Scheme 1, step 2) the most prominent influences.(15) The mechanism of hydrolysis thus varies based on inherent structural attributes, with substrate protonation (SE2 mechanism), carboxonium (carbonylonium) ion formation (A1 mechanism,) or reaction of the protonated form directly with H2O or another nucleophile (A2 mechanism) the rate-limiting step.(15a−d,16) The rate of hydrolysis will depend on the mechanism of the reaction, which can clearly be readily influenced by electronic effects, but steric factors can also play a role, as does substitution pattern and, for cyclic acetals and ketals, ring size.(15e,f,h,16,17) Oxygen basicity will influence the population of the protonated form, while electronic stabilization of the carboxonium (carbonylonium) ion intermediate will promote a faster rate of hydrolysis via the A1 pathway.(15e,f,18) Hence, proximal electron-withdrawing substituents confer higher stability to acetals and ketals by both reducing the extent of protonation and/or destabilizing the carboxonium (carbonylonium) ion intermediate, thereby slowing the rate of dissociation of the alcohol.(17d,19) This is illustrated by the measured equilibrium constants between the series of aldehydes and ketones in H2O, MeOH, or EtOH collated in Table 1, where the data capture the effect of a range of electronic properties on the reactivity of structurally simple carbonyl-containing compounds.(20) For example, while acetaldehyde (Table 1, entry 1) exhibits a keq of 1.06, trifluoro-substitution (Table 1, entry 8) alters the equilibrium in favor of the hydrated form by 4 orders of magnitude; consequently, trifluoroacetaldehyde exists predominantly in the hydrated form in aqueous solution. Two well-known hydrates are chloral hydrate (Table 1, entry 7 and 22), where the carbonyl moiety is activated toward the hydrated form by the adjacent electron-withdrawing chlorine substituents, and ninhydrin (23), where the central carbonyl is activated by the two flanking ketone moieties.(21,22) Chloral hydrate (22) is a sedative/hypnotic agent used before minor medical or dental surgery or as a short-term treatment for insomnia.(21) Ninhydrin (23) is routinely used in forensic investigations for fingerprint analysis that functions by engaging in a chemical process that relies upon the reaction of the central hydrated carbonyl with the amino terminus of amino acids and peptides.(22) Ketals (and aminals) derived from a range of halogen-substituted ketones 24 have been shown to display extraordinary stability toward acid hydrolysis, oxidation, and thermal degradation.(23) For example, 25 and 26 are stable toward hydrolysis in the presence of concentrated H2SO4 at 150 and 170 °C, respectively, and were impervious to treatment with 20% HCl in CH3OH, 6 N HNO3, and 2 N NaOH at 100 °C for extended periods where they could be recovered unchanged.(23) A large series of halogenated 1,3-dioxolane derivatives has been evaluated for anesthetic activity in mice from which only 2-(trifluoromethyl)-1,3-dioxolane (27) demonstrated the targeted profile, although the compound was anticipated to be flammable at concentrations that would be associated with a clinical effect.(24)
Scheme 1
Scheme 1. Mechanism of Hydrolysis of Ketals and Acetals
Table 1. Equilibrium Constants for Addition Reactions of Carbonyl Compounds with H2O and Alcohols(20)
| entry | carbonyl compound | hydration Keq(20a) | hemiacetal Keq(20a) | hydration Keq (NMR data(20b)) |
|---|---|---|---|---|
| 1 | CH3CHO | 1.06 | 0.50* | 1.43 |
| 2 | CH3CH2CHO | 0.85 | 0.42* | 0.7 |
| 3 | CH3COCH3 | 1.4 × 10–3 | 2.2 × 10–4 | 2.0 × 10–3 |
| 4 | CH2ClCOCH3 | 0.11 | 2.7 × 10–2 | 0.1 |
| 5 | CHCl2COCH3 | 2.9 | 8.1 × 10–2 | 2.86 |
| 6 | CH2ClCHO | ND | ND | 370 |
| 7 | CCl3CHO | ND | ND | 2.78 × 103 |
| 8 | CF3CHO | 2.9 × 104 | 1.2 × 103 | ND |
| 9 | CF3COCH3 | 35 | 0.88 | ND |
| 10 | CF3COCF3 | 1.2 × 106 | 3.0 × 103 | ND |
| 11 | C6H5COCF3 | 78 | 270** | ND |
| 12 | CH3COCOCH3 | ND | ND | 2.0 |
| hemiacetal Keq measured in MeOH except * (EtOH) and ** (H2O) | hemiacetal Keq measured in H217O | |||
The data presented in Tables 2–4 captures the relative and absolute rates of hydrolysis for a series of structurally simple acetals and ketals that offer some instruction for the purpose of drug design, although there are additional molecular modifications that can influence stability and which will be discussed later (vide infra).(15a,e,f,17c) Increasing substitution at the carbon located between the two oxygen atoms increases the rate of hydrolysis, as evidenced by the comparison between 28, 29, and 30 in Table 2 where the Me in 30 increases the hydrolysis rate by 37,000-fold; and 33 and 34 where the Me in 34 enhances the lability by almost 26,000-fold.(15e) Similarly, in the series of dioxolanes 35–37, hydrolytic degradation rates increase with substitution at the methylene.(15h) While this was attributed to a steric decompression factor that captures the effect of the collapse of a tetrahedral intermediate to a trigonal alkoxy carboxonium (carbonylonium) ion intermediate, electronic stabilization of the carboxonium (carbonylonium) ion is presumably also a contributing factor. A higher substituted alkoxy element also enhances the rate of hydrolysis, attributed to the increased basicity (proton affinity) of the oxygen atom, as illustrated by the 10-fold difference in rate between the EtO in 32 and the MeO in 31 in Table 2 and 39 and 40 in Table 3. Smaller rings are more stable toward hydrolysis than larger rings (compare 41, 42, and 43 in Table 3) while integrating one of the oxygen atoms as part of an aryl ether moiety slows the rate in the context of a smaller ring (compare 44 with 41, and 45 with 42 in Table 3) but not the larger ring, as illustrated by the comparison between 47 and 43.(10c) In these examples, the hydrolysis rates correlate with proton affinity values. In addition, substituents in the embedded diol can slow the hydrolysis rate, as illustrated by the data compiled for 48–53 in Table 4.(17c)
Table 3. Relative Rates of Hydrolysis of a Series of Acetal and Ketal Derivatives Indexed to Spiro[benzo[d][1,3]dioxole-2,1′-cyclohexane] (44)(15f)
Table 4. Measured Rate Constants for the Hydrolysis of the Series of Ketal Derivatives 48–53(17c)
For the series of benzophenone ketals 54–58 compiled in Table 5, a good correlation between the log of the rate of hydrolysis and the Hammett σ constant but a poor correlation with Brown’s σ+ constant was interpreted to indicate that the reaction was associated with substrate basicity (A1 or A2 mechanism) rather than carboxonium (carbonylonium) ion stabilization (SE2 mechanism).(15a,25) This provided an explanation of the observation that the hydrolysis of benzaldehyde diethyl acetal was more rapid than that of benzophenone diethyl ketal, which reacts via an SE2 mechanism.
Table 5. Measured Rate Constants for the Hydrolysis of the Series of Benzophenone-Based Ketal Derivatives 54–58(15a)
Drugs and Molecules Incorporating Nonstabilized Acetals and Ketals
Topiramate
One of the most prominent orally bioavailable, ketal-containing drugs is the anticonvulsant topiramate (20) which incorporates two acetone-derived ketal moieties, with one of the dioxolane rings integrated into a third ketal element by virtue of its relationship with the pyran ring.(12) Topiramate (20) is a derivative of the naturally occurring monosaccharide d-fructose and was originally prepared as a synthetic precursor to fructose-1,6-diphosphate analogues designed to block glyconeogenesis. Interestingly, 20 was selected for evaluation as an anticonvulsant in a traditional seizure test conducted in mice simply because it contains the primary sulfonamide group that is a hallmark of acetazolamide (59), a clinically effective anticonvulsant that was introduced in 1952. Indeed, topiramate (20) demonstrated anticonvulsant properties following oral administration to mice in this model. However, the advancement of topiramate (20) was not without its challenges, as enunciated recently by its inventor Bruce Maryanoff: “As the inventor of topiramate, which contains two ketal groups, I have to say how much flack I caught in trying to champion clinical development of the compound. Bunch of naysayers out there, with inherent chemical prejudices. We verified its stability to simulated gastric fluid, and the rest is history: a billion-dollar drug!”(26)
Topiramate (20) was discovered in 1979 and approved by the FDA in 1996, with peak annual sales reaching $2.2 billion as a proprietary drug. In generic form, 20 ranked 89th in sales in the U.S. in 2021 with over 8.5 million annual prescriptions.(27) The 4,5-acetone-derived ketal of 20 is critical for its pharmacological activity since removal (60) or expansion to a cyclohexane ring (61) eliminates the anticonvulsant activity.(28) Despite its low LogP value of 0.5 (a LogP value of 2.0 is optimal for crossing the blood–brain barrier) and relatively high topological polar surface area (TPSA) of 116 Å2 (60–70 Å is optimal for CNS drugs) primarily due to the presence of the primary sulfonamide moiety, 20 readily penetrated the central nervous system (CNS).(29,30) In patients with epilepsy, the median cerebrospinal fluid (CSF)/plasma ratio of total 20 was 0.85.(31) The unbound fraction of 20 in plasma was 84%, while the free fraction in CSF was 97%, and the concentration of 20 in CSF was approximately the same as the unbound proportion of the drug in plasma. Therefore, the plasma concentration of 20 can be used for therapeutic drug monitoring. Interestingly, the hexafluorinated analogue 62, which was prepared to assess the effect of increased lipophilicity on CNS penetration rather than to modulate chemical stability, exhibited poorer activity in the mouse maximal electroshock seizure model screen, with only 40% protection observed at a dose of 75 mpk, which compared to 80% for 20 at a dose of 10 mpk.(28) In humans, the oral bioavailability of 20 is 80%, with the majority (70%) of the drug excreted unchanged in the urine, and the drug has a half-life in plasma of 21 h. In preclinical species (mouse, rat, rabbit, and dog), 89–98% of the dose of 14C-labeled 20 is recovered unchanged in the urine and feces.(32) The remainder of the drug is metabolized, which includes the loss of both ketal elements, with some hydrolysis occurring in the gut during absorption; however, the collective PK data quoted above suggest that hydrolytic decomposition of 20 in the gut is minimal.(32)
The precise mechanisms underlying the pharmacological actions of 20 toward relieving seizures and migraine attacks have not been fully elucidated.(33) However, 20 has been shown to be active on voltage-dependent sodium channels, and both γ-aminobutyric acid (GABA) and glutamate receptors, properties that are likely to contribute to its therapeutic effects. Topiramate (20) enhances GABAergic activity and reduces glutamatergic activity, which attenuates neuronal excitability, thus preventing seizures and migraines.(33) In addition, blocking activity on the voltage-dependent sodium channel may further enhance its antiseizure activity.
Doxofylline
Theophylline (63), which is readily available from natural sources such as tea leaves and cocoa beans, is a bronchodilator that has been used for the treatment of asthma and chronic obstructive pulmonary disease (COPD) since 1930.(34) While effective, theophylline (63) exhibits a narrow therapeutic window, with nausea, stomach and abdominal pain, headache and trouble sleeping among the most common side effects, and is associated with numerous drug–drug interactions (DDIs). Doxofylline (64), which differs from 63 by the presence of a cyclic acetal-containing side chain, demonstrates comparable efficacy in the treatment of respiratory diseases while offering a superior safety profile that is associated with fewer DDIs; notably, 64 exhibits a distinct pharmacological profile to 63.(35) Doxofylline (64) is stable under acidic conditions (0.2% formic acid, 37 °C, 1 h), reflecting the 63% oral bioavailability and t1/2 of 7–10 h observed in humans. The major metabolite in humans is the primary alcohol 67, which is much less active than the parent compound; thus, doxofylline (64) is not considered to be a prodrug of 63 (Scheme 2).(36) A recent study showed that the aldehyde 66 was the most abundant metabolite produced in human liver microsomes (HLM). However, in human plasma, the major metabolites were the alcohol 67 and the carboxylic acid 68, with the aldehyde 66 and the 2′-hydroxyethyl ester of theophylline acetic acid 69 identified as minor components. Thus, the metabolic pathway for 64 in humans involves the CYP450-mediated oxidation of one of the methylenes of the dioxolane ring to afford 65, which precipitates ring opening and collapse of the acetal to give the aldehyde 66, which is either reduced to the alcohol 67 or oxidized to the acid 68 by non-P450 dismutase in the cytosol.(36a) The 2′-hydroxyethyl ester 69 was also observed after incubation with rat liver microsomes (RLM) and was the major metabolite in this experiment, which presumably arose from cytochrome P450 (CYP450)-induced oxidation of the dioxolane at the C2 methine to afford 70, which is subject to spontaneous ring opening.(36b)
Scheme 2
Scheme 2. Metabolism of Doxofylline (64)
SSR411298
SSR411298 (71), a potent, reversible inhibitor of fatty acid amide hydrolase (FAAH), is constructed on a 1,3-dioxane heterocyclic ring as the central core element, a structural feature that distinguishes it from other FAAH inhibitors.(37) FAAH is the primary enzyme responsible for degrading the endocannabinoids anandamide (AEA), oleoylethanolamide (OEA), and palmitoylethanolamide (PEA), and oral administration of 71 elicited robust increases in hippocampal levels of AEA, OEA, and PEA in mice. SSR411298 (71) demonstrated significant efficacy in several animal models of anxiety and depression following oral dosing, although details on the PK profile and chemical stability under acidic conditions were not described. SSR411298 (71) was advanced into clinical trials, but a phase II evaluation of the drug for the treatment of pain associated with cancer was terminated in 2010 for strategic reasons, while clinical development for the treatment of depression was discontinued in 2012 after completion of a second phase II study.(38)
GSK 2336805 (HCV NS5A Inhibitor)
GSK2336805 (72) is a structural homologue of daclatasvir (73), a hepatitis C virus (HCV) NS5A replication complex inhibitor that demonstrated potent activity toward a range of clinically relevant genotypes (GTs) and was developed to be used in combination with other drugs to treat HCV infection.(39,40) The differentiating structural element between 72 and 73 is the spiro dioxolane moiety installed on one of the pyrrolidine rings of the former compound.(40) GSK2336805 (72) exhibited inhibitory activity toward wild-type (WT) HCV replicons representing several genotypes that were comparable to 73, but the cyclic ketal analogue appeared to be more potent toward several viruses expressing mutations in the HCV NS5A protein. GSK2336805 (72) was advanced into phase II clinical trials to assess its pharmacokinetic (PK) profile in normal healthy volunteers (NHVs) and its effect on viral load in HCV-infected subjects. In clinical trials, 72 demonstrated inferior oral exposure compared to 73, which was a result of its limited oral absorption rather than presystemic degradation of the ketal moiety.(40b) GSK2336805 (72) accounted for more than 95% of the total drug-related material in human plasma extracts, with two metabolites estimated to account for between <1% and <5% of the dose, respectively, dependent on the dosing regimen. One of the characterized metabolites of 72 was the result of hydroxylation of the unsubstituted pyrrolidine ring adjacent to the ring nitrogen atom at the C5 position, the main path of metabolism for 73, while the other reflected modification of the dioxolane moiety in a fashion attributed to hydrolysis to the ketone which was subsequently reduced to the alcohol; however, this metabolite amounted to <1% of drug-related material following doses of 75 and 120 mg.(40b)
HCV Replication Inhibitors
A series of imidazo[1,2-a]pyridine-based HCV replication inhibitors that appeared to target the NS4B protein and originated with the oxazolidinone-substituted piperidine 74 was developed to incorporate the substituted piperazine amide motif found in 75.(41) The single-crystal X-ray structures of both 74 and 75 revealed a perpendicular orientation of the two cyclic ring systems that, in each case, was calculated to be the lowest energy conformation. Against this backdrop, a spiro ketal moiety was designed as a means of constraining the two ring systems in a mutually orthogonal arrangement anticipated to mimic the preferred conformation. Spiro ketal 76 showed comparable inhibitory activity to the original lead compounds, but its oral bioavailability was moderate due to CYP450-mediated hydroxylation of the piperidine ring on the carbon atom α- to the ketal moiety. This metabolic modification afforded the hydroxylated metabolite 77, which exhibited both enhanced antiviral potency and excellent oral bioavailability.(41) The discovery of these novel spirocyclic compounds as potent HCV NS4B inhibitors demonstrates that spiroketalization can be an effective tool for influencing conformation while offering facile synthetic accessibility and, in this context, excellent oral bioavailability in rats.
Proline Acetal-Based Macrocyclic HCV Inhibitors
The pentapeptide-based ketoamide 78 was identified as a lead mechanism-based HCV NS3/4A protease inhibitor with moderate potency, Ki* = 220 nM.(42a) An X-ray cocrystal structure revealed close proximity of the tert-butyl group bound to the S2 proline and the Boc capping moiety that extends into the P4 subpocket, suggesting the potential for macrocyclization between these two elements that would preorganize the molecule into the preferred conformation.(42b) To test this hypothesis, a substituted bicyclic proline acetal moiety was introduced at S2 while a 2-(3-hydroxyphenyl)acetamide cap at S3 provided a convenient synthetic handle with which to link to the S2 element via a Mitsunobu reaction. These efforts led to the identification of the three macrocycles 79–81, where the S2′ moiety was the site of structural variation, with all demonstrating potent enzyme inhibitory activity.(42b) An analysis of the X-ray cocrystal structure of 80 bound to HCV NS3/4A protease indicated that hydrophobic interactions between the S2 bicyclic proline acetal and the protein surface contributed to the excellent potency of the inhibitor. However, the PK properties of these acetal-based macrocycles were not described.
Cyclophilin HCV Inhibitors
The nonimmunosuppressive cyclophilin (Cyp) inhibitor 82, derived from the naturally occurring sanglifehrins that incorporate an unusual piperazic acid moiety, was the basis of an optimization campaign designed to identify a potent HCV inhibitor with oral bioavailability and appropriate PK properties.(43,44) To improve the antiviral and PK profiles of 82, three structural modifications were performed: the styrene element was replaced with a quinoline heterocycle, in which the olefin is incorporated into the phenyl ring of the fused bicyclic moiety; the macrocycle was reduced in size to a 21-membered ring; the C1–O24 lactone and N12–C13 lactam elements were transposed.(44) The latter molecular edit introduced an amide H-bond donor at a site where it could engage the proximal quinoline nitrogen atom in an intramolecular interaction, thus leading to significantly improved membrane permeability and high oral absorption. The C14 geminal dimethyl substituents provided steric bulk to reduce the propensity of esterases to hydrolytically open the lactone ring. The resulting analogue 83 showed excellent oral bioavailability in rats and dogs but suffered from moderate to high metabolic clearance and was a significant activator of the pregnane X receptor (PXR).(45) Cyclization of the geminal dimethyl in 83 to form the spirocyclic 1,3-dioxane found in 84 reduced the measured LogD value from 3.2 to 2.2, a structural edit that conferred lower PXR activation (45% compared to 88% at 15 μM) and improved metabolic stability (predicted human clearance was 0.42 L/h/kg compared to 0.68 L/h/kg). 2-Substituted 1,3-dioxane analogues were not described, presumably because they might be anticipated to be less desirable since 2-methyl- or 2,2-dimethyl-1,3-dioxanes would increase the LogD while significantly reducing the stability of this moiety under acidic conditions (the relative rates of acid-catalyzed hydrolysis of 1,3-dioxolane (35), 2-methyl-1,3-dioxolane (36) and 2,2-dimethyl-1,3-dioxolane (37) are 1:5,100:54,000 (Table 2)).(15h)
Glycine Transporter Inhibitors
In the development of a series of 3,4-disubstituted pyrrolidine sulfonamides as glycine transporter 1 (GlyT1) inhibitors, the 4-fluorophenyl substituent at C3 of the pyrrolidine ring of 85 was replaced with a dioxane ring in 86 as an approach to reducing the overall lipophilicity of the molecule.(46) In this series, lipophilicity correlated well with intrinsic clearance values obtained from liver microsomal studies. The cLogP of dioxane 86 was reduced by almost 3 units compared to the fluorophenyl prototype 85, resulting in a significant reduction in clearance in both HLM and RLM, which translated into a modest increase in oral bioavailability in rats from 25% to 35%. In order to allay concerns about the stability of the dioxane moiety under low pH conditions, 86 was incubated at pH = 1 for 2 days at room temperature with no appreciable amount of hydrolysis observed. The drug developability trends observed with 86 are consistent, in part, with the increase in the fraction of sp3 carbon atoms (Fsp(3)), which has been advocated as a metric for drug-likeness.(47)
Benzodioxole Derivatives
The benzodioxole moiety is a common structural element present in many natural products, as exemplified by piperine (87), the rich flavor in black pepper and long pepper.(48) However, despite being an acetal, the benzodioxole moiety does not appear to have caused overt concern with respect to the hydrolytic potential within the medicinal chemistry community.(15e,f) A benzodioxole element is also embedded in several marketed drugs including the antidepressant paroxetine (88), the phosphodiesterase 5 (PDE5) inhibitor tadalafil (89) used for the treatment of erectile dysfunction, and the anticancer agent etoposide phosphate (90).(49−51) While chemical stability does not appear to be an issue, there are two potential liabilities associated with the benzodioxole moiety in drug discovery and development. First, CYP450 enzymes can metabolize the methylenedioxy moiety to a highly reactive carbene intermediate which binds very tightly to the heme iron atom forming a stable, metabolic intermediate (MI) complex that only slowly dissociates (Scheme 3).(49,52) This can be a source of drug–drug interactions with other medications that are metabolized by CYP450 enzymes. Second, when the MI complex dissociates, a catechol is released, which can undergo CYP450-mediated oxidation to afford an ortho quinone, a reactive alkylating agent that can be a source of toxicity (Scheme 3).(49) One approach to stabilizing the methylenedioxy moiety involves fluorination of the acetal CH2 and the 2,2-difluorobenzodioxole moiety is a feature of the cystic fibrosis transmembrane regulator (CFTR) correctors lumacaftor (91) and tezacaftor (92), drugs that are used to treat cystic fibrosis.(53) This moiety is also deployed in JNJ-42165279 (93), a potent and selective inhibitor of FAAH that is being explored as a treatment for depression, and the camptothecin analogue 94, which was explored as a potential antitumor agent in the context of its prodrug 95.(54,55)
Scheme 3
Scheme 3. Metabolism of the Benzodioxole Moiety Leading to CYP Enzyme Inhibition and the Production of Catechol and ortho-Quinone
The substituted benzodioxole 96 was identified as a novel cannabinoid-1 receptor inverse agonist explored for its potential to treat obesity.(56) Based on molecular modeling of the lead compound 96 and the previously known cannabinoid-1 receptor (CB1R) ligand 97, the para-fluorophenyl residue in 96, which was not critical for binding, was truncated to arrive at the sulfonamide 98, a molecular edit associated with a 6-fold reduction in binding affinity. However, the sulfonamide series, in general, suffered from poor metabolic stability, but the transformation of 98 (hCB1R Ki = 38 nM) to the amide 99 (hCB1R Ki = 28 nM) maintained binding affinity. In an effort to reduce lipophilicity, the central phenyl ring was replaced with a pyridine heterocycle to give 100, which showed both improved binding affinity and aqueous solubility. Despite its attractive potency, the pyridyl series could not be progressed due to instability in weakly acidic media. The instability may result from the presence of the electron-deficient pyridine heterocycle, which, upon protonation, promotes dioxolane ring cleavage to afford a carboxonium (carbonylonium) ion 103 that is stabilized by the two phenyl rings and the enamine moiety (Scheme 4). Intermediate 103 can readily hydrolyze to afford a stable hydroxypyridone 104, providing an example where the properties of acetals and ketals need to be considered holistically in the broader context of molecular structure. Indeed, exchanging the pyridine heterocycle of 100 for a C6-substituted fluorophenyl ring (101) improved hydrolytic stability along with both binding affinity and functional activity as an inverse agonist. The introduction of a fluorine and a 2,4-dichloro substitution pattern to the phenyl rings to give 102 further enhanced chemical stability while also improving metabolic stability by ameliorating oxidative modification of the unsubstituted phenyl ring. Moreover, the two chlorine substituents increased lipophilic interactions with the CB1R binding pocket, thus leading to enhanced potency. The benzo[d][1,3]dioxole derivative 102 elicited a robust, dose-dependent reduction in body weight gain in a 16-day diet-induced obesity rat model following oral administration.(56)
Scheme 4
Scheme 4. Potential Pathway for the Acid-Catalyzed Degradation of [1,3]Dioxolo[4,5-c]pyridine 100
Benzylidene Ketals
Selective muscarinic M2 receptor antagonists have been explored for their potential to treat Alzheimer’s disease, with an interesting series represented by 105 and 107 constructed on a benzylidene ketal scaffold.(57) Of particular note for this chemotype, the ketal 105 was found to be 50-fold more potent than the tetrahydrofuran homologue 106. To assess the issue of chemical stability, 105 was treated with 0.1 N HCl solution for several days, with both the ketal and the benzodioxole moieties remaining intact. In this molecule, the electron-withdrawing sulfone substituent contributes to the observed stability of the ketal functionality of 105 by destabilizing the carboxonium (carbonylonium) ion intermediate 108, further illustrating the need to view a molecule and its functional group connectivity holistically. However, the presence of the basic piperidine may also play a contributory role by forming a salt that will reduce the propensity for protonation of the ketal oxygen atoms. Compound 105 showed good exposure in rodents following oral dosing but poor plasma concentrations in monkeys due to CYP450-mediated cleavage of the benzodioxole moiety, which was addressed by replacing with a p-methoxyphenyl substituent to afford 107.(57)
Miscellaneous Acetals and Ketals
2,2,-Diphenyl-substituted dioxanes and dioxolanes have found application as 5-hydroxytryptamine 1A (5-HT1A) receptor agonists, as represented by 109 and 110, with the latter demonstrating a robust analgesic effect in the formalin and hot plate mouse models of pain following IP administration.(58) Because of its lack of interaction with μ opioid receptors, 110 may be useful in the treatment of acute and chronic pain without the side effects that are typically observed with opioid medications. The achiral 109 was orally bioavailable in rats and readily penetrated the CNS, with a peak concentration of 157.9 nmol/g following a 10 mpk oral dose and a brain to plasma ratio of 420.(58a) In rat models of disease, 109 demonstrated anxiolytic and antidepressant effects following oral doses ranging from 5 to 20 mpk and exhibited an antinociceptive activity in mice following IP dosing at 10 mpk, an effect reversed by a selective 5-HT1A receptor antagonist.(58a)
Guanethidine (111) and guanadrel (112) are orally active, postganglionic adrenergic blocking agents that act by displacing norepinephrine from storage granules in nerve endings and are used as step II or step III drugs for the treatment of hypertension.(59a) Despite some structural similarities, these two molecules exhibit different pharmacokinetic properties. For example, the oral bioavailability of 111 is poor and highly variable, with only 3- 50% reaching the systemic circulation, while 112 demonstrated rapid and nearly complete oral absorption.(59b,c) The difference in t1/2 between the two drugs in humans is also significant, at 12 h for 112 compared to 1.5 days for 111. Both drugs are comparable in efficacy for the treatment of mild to moderately severe hypertension; however, 112 elicited less orthostatic dizziness and diarrhea than 111.(59c) Guanadrel (112) is partially metabolized by the liver to give 2-(2,3-dihydroxypropyl)guanidine (113), but nearly 50% of an orally administered dose appears as unchanged drug in the urine.
Cyclic acetals have also attracted the attention of the agricultural chemical industry with benzpyrimoxan (114), an insecticide that is active toward brown rice planthopper nymphs that extends to strains resistant to existing insecticides, a recent and prominent example.(60) The discovery of 114 began with the pyrimidine 115, which demonstrated an IC90 of 2–10 mg/L in protecting rice seedlings against a brown rice planthopper challenge.(60a) Systematic SAR studies around the phenyl ring and its relationship with the pyrimidine and the 4-position of the heterocycle provided 114, which exhibited an IC90 of 0.3–1 mg/L in the primary assay. However, 114 distinguished itself by virtue of its superior ability to protect plants from brown rice planthopper nymphs for extended periods of time following seedling exposure, referred to as residual efficacy, compared to the standard insecticide agent buprofezin (116) used as a control.(60a) The mode of action of 114 was not definitively determined, but symptoms suggested an effect on the insect growth regulator in a fashion that is distinct from that of 116, which is an inhibitor of chitin synthase.
JNJ-10397049 (117) is a potent and selective orexin (OX) 2 antagonist that was identified after optimization of the screening hit 118.(61a) However, 117 demonstrated poor oral bioavailability in preclinical species, which was attributed to the acid lability of the 2,2,-dimethyl-1,3-dioxane heterocycle in the gut, a property viewed as a significant impediment to optimization of the series.(61b) While attention was redirected to an alternative series also derived from a screening lead, the published SAR survey did not describe specific details surrounding the chemical lability of 117 or evaluate variations of the dimethylated ketal that might have enhanced chemical stability at low pH.
There are several cyclic acetal and ketal derivatives with unique structural attributes that may offer potential in drug design but which have not found extensive application. A particularly interesting example is provided by the 3-aza-6,8-dioxabicyclo[3.2.1]octane-based scaffolds 121 and 122, referred to as BTAa (bicycles from tartaric acid and amino acids), which are readily available by the condensation of an amino acid-derived aldehyde 119 with a tartaric acid 120 (Scheme 5).(62) These molecules have been shown to offer useful opportunities for structural diversification and functional mimicry. The absolute configuration at each chiral center can be translated from the absolute configuration of the chiral centers in the starting materials, which yields a family of 8 amido esters 121 that can be selectively reduced to the cyclic amino esters 122, thereby providing access to a second family of 8 architecturally interesting compounds. These molecules have interesting shapes and properties, with the amine nitrogen atom of 122 weakly basic by virtue of its relationship with the electron-withdrawing oxygen atoms, while the ester of 121 is sufficiently activated to readily react directly with amines under mild conditions to afford amides. A primary focus of study with these heterocycles has been an exploration of their potential to act as peptidomimetics. Both 123 and 124 have been viewed as bicyclic mimics of proline 125 that are readily available synthetically from d-Ser and l-Ser, the latter furnishing a d-Pro mimetic. These motifs could also be considered as bicyclic homologues of pipecolic acid. The 3-aza-6,8-dioxabicyclo[3.2.1]octane 126 has been proposed as a potential mimic of a Gly-Asn dipeptide 127 based on the depicted structural comparison, while other studies have focused on their use as scaffolds for turn mimetics.(62c)
Scheme 5
Scheme 5. Condensation of an Amino Acid-Derived Aldehyde 119 with a Tartaric Acid 120 to Afford 3-Aza-6,8-dioxabicyclo[3.2.1]octanes 121 and Their Reduction to Amines 122
The similarity of the shape of the BTAa ring system with tropane and its analogues has also been recognized, explored in the context of dopamine transporter (DAT) inhibitors.(62e) BTAa analogue 128 retained much of the DAT inhibitory potency of the prototypes 129 and 130 but was a much weaker inhibitor of the serotonin transporter (SERT), thereby offering significantly enhanced selectivity.(62e)
Another structurally interesting bicyclic acetal is dihydrolevoglucosenone (131, Cyrene), which is readily available from cellulose in just two chemical steps and is sufficiently robust to act as a dipolar aprotic solvent that has been advocated as a green solvent.(63a) The stability of 131 has been attributed to a double anomeric effect, but the apposition of the ketone moiety will reduce the proton affinity of the acetal oxygen atoms and destabilize the carboxonium (carbonylonium) ion intermediate that would result from dissociation and thus may be a dominant factor. The ketone moiety of 131 is chemically reactive under some circumstances, which would be anticipated to present some limitations to its application as a solvent.(63b) The measured physical properties of 131 reveal a Kamlet–Taft π* value, a measure of polarity/polarizability, of 0.93, which is comparable to N-methyl pyrrolidone (NMP) (0.90), DMF (0.88), and dimethyl acetamide (DMAc) (0.85) but lower than dimethyl sulfoxide (DMSO) (1.00) and sulfolane (0.96), while the H-bonding potential, assessed by the β value of 0.61, is lower than NMP (0.75), DMF (0.71), DMAc (0.73), and DMSO (0.74) but considerably higher than sulfolane (0.30).(63a) These properties calibrate the physicochemical attributes of 131 and its synthetic precursor levoglucosenone (132) that could be of value in understanding how to gainfully decorate and deploy this ring system for applications in drug design.(63)
Biologically Active Acetals and Ketals Derived from Natural Products
Rifamycins
The rifamycins are a family of macrocyclic antibiotics characterized by the presence of a naphthol ring that is convened between an aliphatic bridge with an integrated lactam-ketal moiety as a bridgehead element.(64) Rifamycin B (133) gained prominence as the first member of the family for which the structure was fully characterized (Scheme 6).(65) However, while 133 exhibited little intrinsic antibiotic activity, its spontaneous transformation to an active compound in aqueous solution stimulated further study, which revealed that the molecule underwent stereoselective oxidation to give rifamycin O (134), which, in turn, was hydrolyzed to the highly active antibiotic rifamycin S (135) (Scheme 6).(66) Mild reduction of the quinone moiety in 135 gave the hydroquinone, known as rifamycin SV (136), which showed good inhibitory activity toward Gram-positive bacteria, including Mycobacterium tuberculosis, and moderate inhibitory activity toward certain Gram-negative bacteria.(64,67) Nevertheless, therapeutic application of 136 is limited by inadequate pharmacokinetic properties, particularly very poor oral bioavailability, as well as a narrow spectrum of antibacterial activity. Thus, numerous analogues of 136 have been prepared with the objective of improving both oral absorption and the plasma t1/2 as well as the activity against mycobacteria and Gram-negative bacteria. During these campaigns, the 3-dialkylaminomethyl derivatives represented by 137 as a prototype were exposed to oxidation with Pb(OAc)2 to give 3-formylrifamycin SV (138) (Scheme 6).(68) This compound was an unexpected degradation product that served as a key precursor to a variety of imines, hydrazones, oximes, and hydrazide-hydrazones, a transformation that ultimately led to the discovery of the orally bioavailable rifampicin (139), which has become a cornerstone of tuberculosis treatment and one of the Essential Medicines defined by the World Health Organization (WHO). In patients infected with active pulmonary tuberculosis, a single 600 mg oral dose of 139 exhibited 93% oral bioavailability, and its elimination half-life increased with dose: the elimination t1/2 was 2.6 h following a 300 mg dose, 3.3 h after a 600 mg dose and 5.1 h following a 900 mg dose.(69) Two major active metabolites of 139 that were identified in humans were 138, found in urine, and 25-desacetylrifampicin (structure not shown), which was isolated from both bile and urine.(69) Notably, in both metabolites, the ketal bridgehead remained intact.
Scheme 6
Scheme 6. Structure of 133 and Its Chemical Degradation and Metabolic Pathways
The mode of action of 139 has been determined to be inhibition of bacterial DNA-dependent RNA polymerase (RNAP).(70) A crystal structure of the core RNAP from Thermus aquaticus complexed with 139 revealed no specific H-bonding interactions between either of the two ketal oxygen atoms and the protein; however, the ketal bridgehead along with the aliphatic bridge provided a favorable bioactive macrocyclic conformation to promote van der Waals interactions with hydrophobic side chains proximal to the naphthol ring and potential H-bond interactions with the three polar groups located on the naphthol ring and the two on the bridge element.
Rifabutin (140) is another rifamycin family member commonly used in patients who experience tolerability issues with rifampins, most prominently those infected with HIV-1/AIDS who are taking antiretroviral agents (Scheme 6).(71) Rifabutin (140) demonstrated higher in vitro potency than 139 against rifampicin-susceptible isolates of M. tuberculosis and retained activity toward certain rifampicin-resistant isolates.(71) The pharmacokinetic properties of 140 in humans following a single dose reflect moderate oral bioavailability of ∼20%, likely due to high biliary excretion and significant presystemic metabolism; however, the elimination t1/2 was long at ∼45 h, supporting a once-daily dosing regimen.(72) The two major metabolites of 140 in humans are 31-hydroxy rifabutin (141) and 25-desacetyl rifabutin (142) in which the ketal and the aminal moieties are retained in both, reflecting their resilience in vivo (Scheme 6).
Etoposide and Teniposide
Podophyllotoxin (143), a mitotic spindle poison isolated from the roots and rhizomes of the mayapple (Podophyllum peltatum), has been used for centuries by Native Americans for both its medicinal and poisonous properties.(51) Podophyllotoxin cream is commonly prescribed as a potent topical antiviral agent to treat genital warts (human papilloma virus, HPV) and the poxvirus molluscum contagiosum, but it is highly toxic if taken internally. To overcome the toxicity issue, extensive semisynthetic studies were performed around 143 that culminated in the development of etoposide (144), a 4,6-acetal glucoside derivative of 143 that incorporates both acyclic and cyclic acetal moieties (Scheme 7).(73) Etoposide (144) forms a ternary complex with the enzyme topoisomerase II and DNA, thereby stalling DNA synthesis.(51) In clinical trials, 144 was shown to be effective in the treatment of a wide range of cancers, especially when used as part of combination chemotherapy. However, the clinical application of 144 has been limited by poor inherent aqueous solubility (116–167 μg/mL at pH values of 1.3–8), which contributed to unpredictable absorption with early formulations, believed to be a function of poor drug dissolution rather than issues associated with membrane permeability and absorption.(51,74) The glycoside moiety in 144 appears to be labile at a pH value of 1.3 while the lactone moiety is the source of instability at higher pH (10) values; chemical stability is maximal between the pH values of 5 and 6.15. The degradation half-life of 144 at pH 1.3 is 2.88 h, but at pH 7.30, the compound is very stable, with a half-life of 27.72 days. Thus, the oral bioavailability of 144 is compromised by poor dissolution and instability in the gut, where the pH value is low. In 1994, a team at Bristol Myers Squibb developed the water-soluble prodrug 90, which, although designed for IV administration, increased the oral bioavailability of etoposide to 81%.(75) The phosphate moiety of 90 presumably facilitates rapid dissolution of the prodrug in the gut, which is cleaved presystemically by alkaline phosphatase, an enzyme expressed abundantly on the brush border membrane, with the absorption of the released 144 sufficiently rapid to avoid precipitation or hydrolytic decomposition.(76) Etoposide phosphate (90) has been widely used for the treatment of small-cell lung cancer, testicular cancer, and lymphomas and is included on the WHO’s List of Essential Medicines.
Scheme 7
Scheme 7. Structure of 143, Its Evolution to 144 and 90, and Metabolism of 144
Teniposide (145), which differs from 144 by the presence of a 2-substituted thiophene heterocycle rather than a methyl substituent bound to the glucopyranoside ring, is not significantly more potent than 144 in terms of intrinsic activity, but its enhanced cellular uptake leads to greater drug accumulation within cells, thus resulting in improved cytotoxicity.(51,77) The oral bioavailability of 145 in humans averages 42%, but there is considerable variability between individuals (20–71%).(51,78) However, despite the potential for oral delivery, 145 is only administered through an intravenous infusion. In humans, 144 and 145 can be metabolized by several pathways, including CYP3A4-mediated demethylation of one of the methoxyl substituents on the E ring to give the catechol metabolite 146, which can be further oxidized to a quinone intermediate 147 by cellular oxidases (Scheme 7).(51,78b,79,80) Both metabolites showed comparable potency toward inhibiting topoisomerase II; however, the quinone metabolite 147 has been suggested to contribute to the occurrence of epipodophyllotoxin-associated secondary myeloid leukemia, a serious complication of acute lymphoblastic leukemia (ALL) therapy.(51,79,81)
Cortiscosteroid 16,17-Ketals
The installation of a 16,17-ketal to the core of the anti-inflammatory corticosteroid triamcinolone (148) led to the family of compounds 149–157 that demonstrated increased potency as the result of enhanced binding to a hydrophobic site of the glucocorticoid receptor, with fluoro substituents at C6 and C9 further improving binding affinity and/or selectivity.(14,82) These ketal-based drugs have been used extensively as topical agents to treat a range of skin conditions and as inhaled medications to treat asthma and COPD.(83) The delivery of these ketals by inhalation was developed as an approach to reducing systemic side effects. Regardless of the delivery device used, only a maximum of 10% of the inhaled dose reaches the airways, with the rest of the dose swallowed and absorbed through the GI tract. The drug that reaches the systemic circulation undergoes extensive metabolic inactivation in the liver, as exemplified by budesonide (150), one of the most widely used lung medications in the world.(27) The acetal moiety is hydroxylated at the acetal carbon by microsomal CYP450 enzymes in the liver to afford 158, which sets the stage for spontaneous decomposition to give the hydroxy ester 159 (Scheme 8).(84) Esterase-mediated hydrolysis furnished 16-hydroxyl prednisone (160), an essentially inactive product. When taken orally for the treatment of certain bowel conditions, 150 acts primarily at the local level within the GI tract.(85) In this context, the acetal moiety of 150 not only associates intimately with the glucocorticoid receptor but also functions as a handle for metabolic inactivation in the liver to reduce systemic activity, thereby rendering 150 a soft drug.
Scheme 8
Scheme 8. Metabolism of 150 to Afford 160
9,10-Acetal-Containing Taxoids
Paclitaxel (161) and docetaxel (162) are two of the most important drugs in cancer chemotherapy.(86) However, both compounds are poorly soluble in water, which limits their formulation to detergent-based vehicles such as Cremophor EL (Kolliphor EL) or Tween 80, both of which are frequently associated with untoward hypersensitivity reactions and require preventative premedication with antihistamines or corticosteroids.(87) In addition, both drugs are administered intravenously and are unsuitable for oral use due to poor oral bioavailability. In order to improve the aqueous solubility, a basic amine was introduced onto the 9,10-acetal ring of the paclitaxel homologue 163 using a methylene spacer to afford the morpholine derivative 164 and the dimethylamine analogue tesetaxel (165), where the absence of the C-7 hydroxyl substituent enhances potency.(88a−e) The acetal moiety enhanced antitumor activity, and the side-chain amine contributed to improved solubility and oral bioavailability while also providing a site for protonation that may help to protect the acetal from acid-mediated degradation.(88a−e) Both 164 and 165 significantly suppressed tumor growth over a wide dosage range following both IV and PO administration in a mouse B16 melanoma model. Moreover, administration of the drugs at the same dosage by both routes produced comparable tumor growth inhibition and body weight loss, indicative of excellent oral bioavailability in mice for both compounds.(88d) Thus, in this context, the amine-substituted acetal moiety in 164 and 165 appears to possess chemical and metabolic stability suitable for oral delivery. Tesetaxel (165) was advanced into clinical trials as an orally bioavailable taxane where it was well absorbed and was associated with a long terminal t1/2 of 167 ± 77 h.(88f,h,h) Although 165 demonstrated responses when explored as a second line monotherapeutic agent in patients with nonsmall cell lung cancer, development was recently abandoned after completing several phase 2 clinical trials in HER2 negative breast cancer patients and a phase 3 clinical trial in triple-negative breast cancer patients.(88i,j)
3,6-Ketal Macrolides
Bovine respiratory disease (BRD) is caused by a bacterial infection that adversely affects beef cattle across the globe but can be treated effectively with antibiotic therapy. Although azithromycin (166) exhibits broad-spectrum antibacterial activity and a long tissue half-life and could be an effective therapy, it has not been given consideration for the treatment of BRD because of the potential for the development of drug-resistant bacteria, which may render it less effective in the treatment of community-acquired bacterial infections in humans. In an effort to discover structurally novel macrolide antibiotics, the acid-labile cladinose sugar was removed, and the exposed C3 hydroxyl was hybridized with the proximal C6 hydroxyl to produce a series of 3,6-ketal derivatives.(89) These ketals, which presumably provide conformational constraint in a fashion that complements the binding site, exhibited potent antibacterial activity toward several key veterinary pathogens, including Staphylococcus aureus and Pasteurella multocida. In a mouse model of intramammary infection, 167 and 168 demonstrated clearance of Staphylococcus aureus in most of the murine mammary glands following subcutaneous injection at a dose of 15 mpk.(89) These ketals may be useful in the treatment of dairy cattle mastitis caused by bacterial infections. However, the oral bioavailability profiles of these ketals remain unknown, and in this case, the 3,6-ketals appear to have been explored primarily for the purpose of structural novelty.
Glycosides
While glycosides are susceptible to degradation by glycoside hydrolases and may be labile under acidic conditions, they can, nevertheless, possess adequate oral bioavailability for therapeutic application as represented, for example, by etoposide phosphate (90) (vide supra) and the second-generation macrolide antibiotics azithromycin (166) and clarithromycin (169). Degradation of 166 to the descladinose derivative was observed after both oral and IV administration, with much higher amounts of this product observed after oral dosing due to exposure to stomach acid.(90,91) However, the impact of cladinose cleavage on the oral bioavailability of 166 appears to be rather limited since the major factor responsible for the moderate oral bioavailability (12%) is incomplete oral absorption; rather, the slow and poor absorption may prolong exposure of the drug to the deleterious effects of stomach acid.(91) The presence of the macrocyclic tertiary amine in 166, which contains two acyclic acetal moieties, results in a much longer serum half-life (35–96 h in humans) and exceptional uptake in tissues, particularly in the lungs, where the half-life is 132 h, and tonsil and prostate tissues. As such, a three-day dose pack of 166 is used to treat many different types of infection while 169 generally requires BID dosing for 7–14 days for efficacy.(91)
Cardiac glycosides have been used for centuries to treat patients with heart disease, and the most commonly prescribed drug of this class is digoxin (170), which is obtained from the purple foxglove flower.(92) Despite the potential for lactone hydrolysis, the presence of a trisaccharide moiety that incorporates three acyclic ketal moieties and seven hydroxyl substituents that might be expected to adversely affect membrane permeability, and the high molecular weight (MW = 830), 170 exhibits high oral bioavailability in humans (F = 71%) and is associated with a plasma t1/2 of 36 h.(93a) The major metabolite of 170 in the blood and urine collected from patients is dihydrodigoxin (171) which results from the enzymatic reduction of the olefin located in the lactone moiety, with both the glycosides and the lactone appearing to be relatively stable.(93b) Digoxin (170) is a substrate of both intestinal and renal P-gp and coadministration of drugs that inhibit P-gp can quickly lead to the accumulation of this compound to toxic levels since the drug has a narrow therapeutic index. Because of these potential drug–drug interactions, medication with 170 requires close and careful monitoring.
Phlorizin (172), an O-aryl glycoside natural product found in several fruit trees including apple, cherry, and pear, is a nonselective sodium–glucose-linked transporter-2 (SGLT2) inhibitor that suffers from poor metabolic stability due to its susceptibility to degradation by β-glucosidases in the digestive tract which releases the aglycone phloretin (173), a well-known antioxidant widely used in skin care but which is inactive toward SGLT2 (Scheme 9).(94) While extensive SAR studies were being undertaken to identify analogues of 172 with improved metabolic stability and high selectivity for the SGLT2 transporter, WAY-123783 (174), a nonglycoside pyrazole derivative, was found to demonstrate an antihyperglycemic effect in the db/db mouse model of type II diabetes.(95−97) The pharmacological effect associated with 174in vivo was traced to the formation of the O-glycoside metabolite 175, a compound that was a 3-fold more potent inhibitor of SGLT2 than 172 (Scheme 10).(96,97) However, 175 exhibited only 7-fold selectivity for SGLT2 compared to SGLT1, but this could be enhanced to 180-fold by simply replacing the CH3S substituent on the phenyl ring with an isopropoxy moiety to afford 176. Despite its favorable metabolic stability in a rat intestinal assay and HLM, 176 showed virtually no oral bioavailability in rats (F = 0.4%), which was attributed to its poor membrane permeability (Caco-2 Papp = 1.02 × 10–6 cm s–1) resulting from the presence of 5 H-bond donors (HBDs). To reduce the number of HBDs, the nitrogen atom of the 1H-pyrazole heterocycle was substituted with a range of small alkyl groups from which the N-isopropyl analogue 177 was conspicuous as a potent and selective SGLT2 inhibitor with improved membrane permeability (Caco-2 Papp = 3.16 × 10–6 cm s–1), which contributed to a moderate increase in oral bioavailability (F = 3.2%).(98) To further improve membrane permeability and potentially enhance the intestinal stability of the glucosidic linkage, the 6-hydroxyl group of the glucose moiety was converted to its ethyl carbonate, leading to the discovery of remogliflozin etabonate (178) as a prodrug that exhibited a further increase in oral bioavailability (F = 5.8% in rats; Caco-2 Papp = 4.29 × 10–6 cm s–1).(98) Because of the potency and high selectivity over SGLT1 observed with 177, the carbonate prodrug remogliflozin etabonate (178) was selected for clinical evaluation. Following oral administration, 178 was rapidly absorbed (tmax = 0.5 h; t1/2 = 0.39 h) and deesterified by nonspecific esterases present in mucosal cells of the GI tract to release 177 (tmax = 0.64 h; t1/2 = 1.57 h), which underwent N- and O-dealkylation to give the major active metabolite 176 (tmax = 1 h; t1/2 = 2.68 h) along with small amounts of the inactive 179 (tmax = 1 h; t1/2 = 2.84 h), respectively.(98b,99) Unfortunately, the short plasma t1/2 values of 177 and its active metabolite 176 necessitate a BID dosing regimen, a disadvantage over other SGLT2-inhibiting drugs (QD dosing, t1/2 ≈ 12 h).(99a) Nevertheless, 178 was recently approved in India as a treatment for type 2 diabetes mellitus.(99b)
Scheme 9
Scheme 9. Metabolism of Phlorizin (172) to Phloretin (173) in Vivo
Scheme 10
Scheme 10. Metabolism of 174 to the Glucoside 175 in Vivo
While O-glycosides such as 178 showed reduced glucosidase-mediated degradation and enhanced systemic exposure compared to 172, their poor pharmacokinetic properties prompted further study of SGLT2 inhibitors, which were directed toward C-glucoside derivatives (vide infra).(97)
Fluorinated Thromboxane A2 Ligands
A very effective illustration of the stabilizing effect of electron-withdrawing substituents on acetal stability is provided by the natural product thromboxane A2 (TxA2, 180), which has been the subject of considerable attention due to its central role in a number of pathological states, including angina, thrombosis, and asthma.(100) TxA2 (180) is structurally unique because of the bicyclic acetal motif in which one of the oxygen atoms is part of an oxetane ring, a strained functionality that undergoes facile hydrolytic cleavage at pH 7.4 (t1/2 = 30 s), inherent chemical reactivity that controls the physiological half-life of the molecule. However, the chemical stability of the reactive oxetane acetal motif can be enhanced in a remarkable fashion by the introduction of one or two fluorine atoms into the oxetane ring, as demonstrated by 181-184.(101) For example, the t1/2 of TxA2 (180) at pH 7.4 was prolonged by 105 and 106 by mono- (181) and difluorine (182) substitution, respectively, and the bimolecular rate constant for the hydrolysis of the difluoro-substituted core scaffold 183 is reduced by 8 orders of magnitude compared to the parent molecule 180.(101a−c) The difluorinated core of 182 was combined with the urea β-side chain from known TxA2 antagonists to afford 184 which also functioned as a receptor antagonist. Another approach to improve the chemical stability is to expand the strained oxetane into a tetrahydrofuran ring, as demonstrated by homo-TxA2 (185), which showed no appreciable degradation when stored at −10 °C for 1 year.(101d)
The acetone-derived ketal ICI 180080 (186) was identified as a potent TxA2 antagonist, but chemical stability under acidic conditions was of concern in the context of oral drug delivery.(102) Replacement of the geminal dimethyl ketal substituents of 186 with an ortho-chlorophenyl (ICI 192605, 187) or a trifluoromethyl (ICI 185282, 188) substituent exerted a dramatic impact on the hydrolytic stability at pH = 2. Thus, 187 and 188 exhibited a t1/2 of 19.7 h and 7 years, respectively, compared to 56 s for the lead compound 186. Oral administration of 187 to anesthetized guinea pigs significantly inhibited the effects of a TxA2 agonist on pulmonary function for 6 h, suggestive of good metabolic stability.(102b) The mono-CF3 analogue 188 showed significantly enhanced stability with a t1/2 estimated to be 7 years at pH = 2 at 25 °C, a clear demonstration of the effect of an electron-withdrawing substituent on the hydrolytic sensitivity of acetals.(101a) In order to more fully characterize the stability of 188, studies were conducted at 91 °C where the anticipated hydrolysis of the cyclic acetal was observed to produce not only the triol 189 but also the diol 190. While the degradation rate of 188 declined as the pH increased, plateauing at pH = 5, instability was also observed at pH values beyond 6, where again both the triol 189 and diol 190 were identified as products, although both processes remained relatively slow even at 91 °C (10–6 s–1 at neutral pH and 10–4 s–1 at higher pH at 91 °C compared to 10–10 s–1 at neutral pH and 10–7 s–1 at higher pH at 25 °C). After a detailed kinetic analysis, the mechanism proposed to account for the formation of the diol is depicted in Scheme 11 and invokes the formation of a quinone methide intermediate, either 191 or 193, at both pH values, driven by deprotonation of the phenol (pKa ∼ 9) at high pH which affords 191, with acetal ring opening the rate-determining step.(102a) Reduction of the quinone methide by an intramolecular hydride transfer from the acetal methine would provide diol 192 in a process that requires a conformational change and rotation from the initially produced intermediate to relieve A(1,4) strain between the proton on the ortho position of the oxidized phenyl ring and the allylic substituent, thereby setting the stage for hydride transfer. A simple hydrolytic decomposition of the trifluoroacetic acid ester then leads to the diol 190. Under acidic conditions, 188 is proposed to degrade to the quinone methide 193, an intermediate that generates 194 after the loss of trifluoroacetaldehyde and then the observed triol 189 upon the addition of H2O (Scheme 11).(102a) These observations provide another example of the need to assess the chemical stability and potential degradation pathways of acetals and ketals holistically in the context of the overall structure and its relationship with proximal functionality.
Scheme 11
Scheme 11. Proposed Mechanism for the Hydrolysis of 188 at High pH Values
Fluoroartimisinins
Dihydroartemisinin (DHA, 196), which is the reduced form of artemisinin (195) and incorporates one ketal, one acetal, and one hemiacetal, is an effective antimalarial agent but suffers from a short t1/2 due to chemical instability and type II metabolism via the formation of water-soluble β-glucuronide derivatives which are conjugated at the hydroxyl of the hemiacetal moiety.(103,104) A CF3 substituent was introduced to the hemiacetal carbon to give 197 in a rational effort to increase hydrolytic stability and to reduce the propensity for glucuronidation, which can proceed by the two potential pathways summarized in Scheme 12.(103,105) In pathway 1 in Scheme 12, the CF3 group decreases the nucleophilicity of the tertiary hydroxyl group which renders 197 a poor glycosyl acceptor for 198. In pathway 2 in Scheme 12, the formation of the electrophilic carboxonium (carbonylonium) intermediate 200 is disfavored due to the high energy of this process as a result of the destabilizing effect of the CF3 substituent, which interferes with its reaction with glucuronic acid (201). Taken together, the CF3 substituent blocks both pathways of phase II metabolism, which results in a longer plasma t1/2 and improved oral bioavailability, which translates into enhanced oral activity in models of malaria.(103,105)
Scheme 12
Scheme 12. Potential Hydrolytic Degradation Pathways for 197
Artemether (202), the methyl ether derivative of 196, is another marketed antimalarial agent that also displays a short t1/2 due to the formation of 196 and the glucuronide 205 through either acid-mediated hydrolysis or CYP450-mediated oxidative demethylation via 204 (Scheme 13).(104,105) Once again, the introduction of the CF3 substituent in 203 not only enhanced hydrolytic stability and but also interfered with the oxidative metabolism pathway.
Scheme 13
Scheme 13. Metabolic Pathways for 202
1,3-Dioxane-2-carboxylic Acid Derivatives
Benzafibrate (206) is representative of a class of amphipathic carboxylic acid derivatives collectively described as fibrates that have been prescribed to treat a variety of metabolic disorders, including hypercholesterolemia.(106) These agents act by stimulating the peroxisome proliferator activated receptor-α (PPAR-α), but their agonist activity is weak and nonselective over other nuclear receptors.(107) In an effort to identify compounds with improved potency and selectivity, the conformational constraint of the oxyacetic acid terminus of the lead compound 207 was explored by the formation of the cyclic ketal 208, readily available synthetically by condensing the diol with methyl pyruvate.(108) In this process, the cis-isomer was either the exclusive product or the major isomer. The ester moiety of these dioxanes is known to preferentially adopt an axial orientation stabilized, in part, by a general anomeric effect (GAE) between the lone pairs of electrons on the ring oxygen atoms and the σ* orbital of the C–CO2Me bond.(109) The dioxane 208 was 100-fold more potent than 206 and exhibited greater selectivity over the related PPAR-δ receptor.(108) Methyl substitution of the phenyl ring enhanced both PPAR-α potency and selectivity over PPAR-δ with NS-220 (209), eliciting robust hypolipidemic activity in diabetic mice following oral administration.(108a) Further bioisosteric modification in which the oxazole was replaced with an oxime followed by insertion of a phenyl ring spacer in the alkylene chain led to the orally bioavailable, PPAR-α selective agonist 210 that exhibited superior pharmacokinetic properties.(110) Following oral administration, both 209 and 210 demonstrated antihyperglycemic activity in mouse models of diabetes and antihyperlipidemic effects in rats fed a high cholesterol diet. However, 210 appeared to be much more potent than 209 in both models due to better pharmacokinetic properties (t1/2 = 14 h vs 2 h in rats 30 mpk, PO).(110a)
Morpholine Acetals
A useful and effective strategy to stabilize acetals and ketals is to install a proximal basic amine, as exemplified by the selectivity observed in the acid-catalyzed degradation of the macrolide antibiotic clarithromycin (169) to give the desosamine derivative 211, as depicted inScheme 14. Protonation of the dimethylamine of the desosamine moiety retards additional protonation of the proximal glycosidic oxygen atom, thus enhancing the resistance of the carbohydrate moiety to acid-mediated degradation.(90,111) In contrast, the C3 cladinose glycoside, which lacks a basic amine, is susceptible to hydrolysis.
Scheme 14
Scheme 14. Acid-Mediated Degradation of 169
Although a morpholine heterocycle is only moderately basic (the conjugate acid of morpholine has a pKa value of 8.5, which is 2.6 units lower than for piperidine), it can function to stabilize acetals and ketals. Consequently, morpholine-based acetals have found utility in drug design, with the first application reported in 1996 as part of a search for orally bioavailable NK1 antagonists.(13,112−115) The lead piperidine-based NK1 antagonist 212, although quite potent, suffered from poor oral bioavailability and exhibited a modest affinity for the L-type calcium channel, a potential liability for adverse cardiovascular effects.(114) To address both issues, a significant effort was expended to reduce the basicity of the piperidine nitrogen atom, with two approaches proving to be effective: attachment of an electron-withdrawing heterocycle to the piperidine nitrogen atom linked through a methylene spacer and the introduction of an oxygen atom into the piperidine ring, a molecular edit that led to a morpholine acetal. Both approaches produced compounds with lower basicity than the lead prototype, and as anticipated, these compounds showed only negligible binding affinity for the L-type calcium channel, as exemplified by 213 and 214. When compared with the original piperidine, the morpholine acetal nitrogen of 214 is weakly basic with a measured pKa value of less than 3 in aqueous MeOH compared to 5.3 for the piperidine nitrogen, suggesting that morpholine protonation may play a limited role in enhancing the acid-sensitive stability of the acetal moiety. The reduced basicity of 214 contributed to a 4-fold enhancement in oral activity in the mammalian tachykinin substance P (SP)-induced dermal inflammation (SPIDER) assay in guinea pigs (ID50: 0.009 vs 0.037 mpk for 213).(13) The two major metabolic soft spots of 214 were determined to be cleavage of the benzyl ether and hydroxylation of the phenyl ring, which were blocked by α-methylation of the benzyl group and para-fluorination of the phenyl ring, respectively, to give aprepitant (21), which was approved by the FDA in 2003 to help prevent the nausea and vomiting associated with cancer drug therapy.(13) Aprepitant (21) is prescribed for oral dosing, while the somewhat unusual water-soluble N-phosphoryl prodrug, fosaprepitant (215),was developed for intravenous use.(115) The high stability of morpholine acetals under aqueous acidic conditions is exemplified by studies conducted with 214.(114a) After incubation of 214 in simulated gastric acid at 37 °C for 4 h, neither hydrolysis of the benzyl ether nor isomerization to the trans diastereomer was observed. The stability of 214 toward acid in the GI tract was confirmed by its potent activity in the SPIDER assay following oral dosing to guinea pigs.(114a)
An X-ray cocrystal structure of 21 bound to the NK1 receptor revealed that the exocyclic acetal oxygen atom adopted an axial orientation and interacted as a H-bond acceptor with the side chain amide N–H of Gln165 of the protein (Figure 5A and Figure 5B).(114c) The triazolone oxygen atom engaged in a bifurcated binding interaction with the acid moiety of Glu193 and the NH of Trp184. In the single-crystal X-ray structure of 21, the benzyloxy moiety was also axially disposed, a conformation that minimizes steric strain with the proximal fluorophenyl ring at the 2-position of the morpholine heterocycle while taking advantage of the energy advantage offered by the anomeric effect (Figure 5C).(114d)
Figure 5
Figure 5. A. Key H-bonding interactions between 21 and the NK1 receptor. B. Conformation of 21 bound to the NK1 receptor. C. Single-crystal X-ray structure of 21 (GOPDUK, deposition number 117932 in the CSD).(114c,d)
The discovery of the γ-secretase modulator SPI-1965 (218) as a clinical candidate was highlighted by the replacement of a pendent native sugar of the triterpene glycoside 216 with a morpholine acetal to afford 217.(116) The sugar moiety of 216 contributed to the high TPSA of 155 Å2, a property that strongly correlated with poor CNS permeability. Replacement of the sugar element with a morpholine acetal reduced the TPSA by 32%, leading to significant improvement in both brain penetration and oral bioavailability for 217. Optimization of the morpholine side chain and transformation of the acetate to an ether afforded 218, which is orally bioavailable, brain penetrant, and efficacious at lowering Aβ42 levels in multiple rodent models.(116) In the single-crystal X-ray structure of 218 depicted in Figure 6, the exocyclic oxygen atom of the morpholine acetal adopts an equatorial disposition.(116d)
Figure 6
Figure 6. Single-crystal X-ray structure of 218 (QESQIR, deposition number 1817710 in the CSD).(116d)
Transformation of the native sugar in the antifungal agent sordarin (219) into a morpholine acetal was also explored as an approach to the discovery of semisynthetic analogues with oral bioavailability.(117) Because of its weak antifungal activity and poor pharmacokinetic profile, 219 exhibits only marginal activity in in vivo models of infection. Utilizing morpholine or homomorpholine as a replacement for the glycoside maintained or even increased antifungal potency. Further optimization of the headgroup provided the semisynthetic derivatives 220–223, which displayed superior antifungal activity compared to 219 and enhanced pharmacokinetic properties, with the homomorpholine derivative R-135853 (222) exhibiting 63% oral bioavailability in mice that translated into good oral efficacy in rodent models of fungal infection.(117e)
A weakly basic morpholine acetal was recently exploited as an approach to enhance the brain penetration of a series of BACE1 inhibitors originating from the prototype 224.(118) In this example, both the piperidine in 224 and the morpholine in 225 adopt a similar chair conformation, as revealed by NMR and X-ray crystallographic studies. However, the switch from the piperidine ether 224 to the morpholine acetal 225 increased brain exposure by 5-fold due to the reduced basicity of the core heterocycle, while replacing the cyclohexyl with a tert-butyl further improved both cellular activity and brain penetration in the context of 226.(118) In the cocrystal structure of 226 with the BACE1 enzyme, the exocyclic oxygen atom of the morpholine acetal and the methyl substituent bound to the adjacent carbon atom adopt axial orientations, while the hydroxyethylene bioisostere element is equatorially disposed, consistent with the conformation observed in solution based on NMR studies (Figure 7). The anomeric effect favors the bound conformation of 226, and neither of the oxygen atoms of the morpholine acetal moiety appear to be engaged directly in drug–target interactions.
Figure 7
5-Amino-1,3-dioxanes
2,5-Disubstituted-1,3-dioxanes exhibit a preference for an axial disposition of polar substituents at the 5-position, although the conformational disposition can be dependent on the solvent, as summarized in Table 6 where data are collated for multiple solvents only where a dependence was observed.(119) Notably, protonated amine and trimethylammonium substituents exhibit a strong preference for an axial orientation (entries 1–3) as do NO2, CH3SO2, and CH3SO (entries 4–6) while the nonpolar CH3S prefers to adopt an equatorial disposition (entry 7). In the halogen series (entries 8–10), only fluorine prefers an axial orientation while the disposition of CN (entry 11) is solvent-dependent. The CO2CH3 moiety, carboxylate anion, OCOCH3, OCH3, OCH2CH3, and CH2OCH3 (entries 12–18) all prefer equatorial orientations while the disposition of CH2OH (entry 19) shows solvent-dependence. These preferences have been attributed to the electrostatic attraction between the substituent and the ring oxygen atoms.(119)
Table 6. Energy Differences between the cis- and trans-Isomers of Substituted Dioxanes that can Equilibrate under Acidic Conditions
5-Amino-1,3-dioxane derivatives offer interesting physicochemical properties that were first appreciated by medicinal chemists in 1999 as part of a study of orally bioavailable somatostatin receptor (SSTR) agonists for the treatment of acromegaly, a disorder that is the result of excessive growth hormone release by the pituitary gland.(120) The lead compound in the series, lysine derivative 227, was a potent SSTR-2 agonist but lacked oral bioavailability due to poor absorption. The 5-amino-1,3-dioxane ring in 228 was incorporated as a lysine surrogate, thus eliminating the ester moiety while also reducing the basicity of the primary amine. This molecular edit improved aqueous solubility and oral absorption, which contributed to superior oral bioavailability. However, SSTR-2 agonist activity was reduced by 4-fold but could be restored by introducing a second phenyl ring to the side chain, as in 229, which led to an additional enhancement of oral bioavailability.(120)
More recently, this amino acetal moiety has been incorporated into G-5555 (232), a selective PAK1 kinase inhibitor examined for its potential to treat cancer and other diseases.(2) The combination of a basic amine and high lipophilicity in the lead compound 230 led to significant inhibitory activity toward ion channels, including the human ether-à-go-go-related gene (hERG) cardiac potassium channel, while poor membrane permeability was an additional concern. It is known that hERG ion channel liability can often be attenuated by either reducing basicity or lowering lipophilicity. The replacement of two methylenes in the cyclohexane of 230 with oxygen atoms to form an acetal simultaneously addressed both concerns: the calculated pKa (cpKa) of 10.4 for 230 was reduced to 7.7 in the prototype 231, while the cLogP value declined from 4.5 to 2.4. The combination of effects resulted in a 5-fold reduction in hERG inhibitory potency and a 4-fold enhancement in membrane permeability. Further optimization delivered G-5555 (232) as a potent and orally bioavailable PAK1 kinase inhibitor with only negligible hERG inhibition. The acetal functionality in these compounds was shown to be stable under acidic conditions at pH 1 for 24 h at room temperature.(2)
A cocrystal structure of 232 in complex with PAK1 kinase showed that the 5-amino-1,3-dioxane ring adopted a chair conformation in which both substituents were equatorially disposed, a topographical arrangement that allowed the amine to engage in H-bonding interactions with the backbone carbonyl of Asp393 and a H2O molecule, the latter a bridge to the side chain C═O moiety of Asn394. The alternative conformation would place both substituents in an axial orientation which can, in some circumstances, be favored for amine, stabilized by electronic effects and the potential for intramolecular H-bonding interactions to the ring oxygen atoms, as depicted in the alternate conformation.(119) The conformation of 232 in the cocrystal presumably reflects the spatial arrangement necessary for the amine to engage in H-bonding interactions with the PAK1 enzyme.(2)
A similar strategy has recently been adopted to reduce the hERG ion channel inhibition observed in a series of novel bacterial type II topoisomerase inhibitors (NBTIs) investigated as antibacterial agents.(121) In this example, the hERG inhibition associated with the dioxane-linked compounds 233 and 235 was 20-and 10-fold less potent than the corresponding cyclohexane-linked analogues 234 and 236, respectively. Replacement of the basic secondary amine in 235 with a secondary carboxamide (237) further reduced hERG inhibition while maintaining potent inhibitory activity toward S. aureus. Finally, installation of a 3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide heterocycle to replace the 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide moiety of 237 afforded 238, a potent NBTI and antibiotic agent with MIC values of 0.125 μg/mL toward both methicillin-susceptible (MSSA) and -resistant (MRSA) S. aureus.(121b) However, detailed chemical stability studies and the in vivo performance of these compounds have not been described.
While 2-alkyl-1,3-dioxan-5-amines have been shown to demonstrate resilience toward acid hydrolysis, a 2,2-dialkyl-1,3-dioxan-5-amine has been utilized as a prodrug moiety in 240, which releases the parent amino diol fingolimod (FTY720, 239) in the mildly acidic environment of endosomes where the pH is ∼5.0.(122) This prodrug concept was designed to avoid systemic phosphorylation of 239 to its active metabolite which causes immunosuppression by activating the sphingosine-1-phosphate receptor 1 (S1P1) but which is also associated with lymphopenia and bradycardia. The introduction of the polyethylene glycol (PEG) moiety enhanced the aqueous solubility of the prodrug, which is taken up by cancer cells where 239 is released in the endosomal compartment and induces metabolic stress.(122) The potential of the prodrug 240 to release 239 was assessed by incubation at 37 °C in 10 μM deuterated acetate and tris buffers at pH 5.0 and 7.4, with prodrug integrity followed by 1H NMR. At pH = 5, 80% of prodrug 240 had degraded to release 239 after 28 h of incubation while the molecule was completely stable at the physiological pH of 7.4. This observation was interpreted based on the change from a hydrophobic molecule to one that is more hydrophilic upon protonation.(123) In this case, the presence of the amine facilitates hydrolysis, which appears to be inconsistent with the internal protection concept of the amine in the amino acetal, as in compound 232. However, in this case, the acid sensitivity may be promoted by the protonated primary amine substituent preferentially adopting an axial conformation that facilitates activation of the ketal toward hydrolysis by engaging the oxygen atoms in an intramolecular H-bonding interaction.(119) Nevertheless, additional studies are needed in order to more fully understand the factors that have an impact on the acid stability of these amino acetal- and amino ketal-based systems.
While the stability of the 5-amino-1,3-dioxane moiety toward acidic hydrolysis can be modulated by the presence of the mildly basic amine, which will more readily accept a proton than the acetal moiety, a basic moiety is not an essential prerequisite for oral bioavailability.(124) A series of carbamates derived from a 2-phenyl-1,3-dioxan-5-amine core scaffold 241, represented by 242 and 243, has been shown to demonstrate efficacy in a xylene-induced ear edema mouse model of inflammation following oral administration.(124) These cyclic acetals did not function as prodrugs since the corresponding aldehydes and aminodiols were inactive in the respective animal studies. In this series, biological activity was found to be independent of the relationship between the dioxane substituents, with both the cis- and trans-isomers effective in vivo, as exemplified by 241 and the comparison between 242 and 243. In these molecules, the C5 amine and carbamate functionalities are oriented in axial conformations regardless of the relative configuration of the phenyl substituent at C2. In the case of 242 and 243, a hydrogen-bonding interaction between the carbamate NH and the heterocyclic oxygen atom may additionally contribute to the stability of the axial conformer.
Another interesting example of the stability of a nonbasic 5-amino-1,3-dioxane moiety toward acid hydrolysis is provided by the maleimide-based linkers 244–247 explored for application in the design of antibody–drug conjugates (ADCs) where a replacement for the hydrophobic cyclohexane in 248 was sought to improve aqueous solubility.(125) The stability of these moieties to hydrolytic degradation was assessed in the context of the series of fluorescence resonance energy transfer (FRET)-based probes 244–248 compiled in Table 7. In these molecules, the fluorescence of the tetramethylrhodamine (TAMRA) fluorophore is quenched by the proximal BHQ element when intact, but rupture of the molecule will lead to an increase in fluorescence. Incubation of these molecules at pH values ranging from 2 to 9 in buffers resulted in no more than a 10% increase in fluorescence, reflective of excellent stability under these conditions, thus meeting the criteria of a noncleavable linker. Degradation was only observed under the strongly acidic conditions associated with aqueous 1 M HCl, with the rates compiled in Table 7.(125a) The 1,3-dioxane linker provided slightly better chemical stability than the homologous dioxolane (compare 246 with 244 and 247 with 245) which can be attributed to the effects of the ring size of the cyclic acetal.(15i,17c) The dioxane 244 exhibited comparable stability to the cyclohexane prototype 248 in human plasma and in a variety of aqueous buffers, while the dioxolane 246 was slightly less resistant to degradation. However, the rupture of these molecules to produce fluorescence is complex, with a retro-Michael addition of the thiol to the maleimide moiety a potential contributor. While the detailed comparison between 244 and 248 revealed the superiority of the former, some of the advantages were attributed to more facile ring opening of the maleimide moiety in 244, which would stabilize the molecule toward a retro-Michael elimination of the BHQ-2 thiol element and preserve fluorescence quenching.(125a) This is presumably a function of the less basic amine embedded in 244 compared to 248, which facilitates imide hydrolysis.
Table 7. Measured Rate Constants for the Degradation of the Series of FRET-Based Probes 244–248 under Acidic Conditions
Basic Heterocycle-Containing Acetals and Ketals
In addition to basic amines, mildly basic heteroaryl rings can also contribute to enhancing the stability of proximal acetals. Two well-known examples are provided by the antifungal agents ketoconazole (249) and itraconazole (250), which exhibit good to excellent oral bioavailability in humans.(126−128) Ketoconazole (249) was the first orally bioavailable, broad-spectrum antifungal medication licensed, but the oral tablet has been discontinued in many countries due to the potential for this drug to cause severe but idiosyncratic liver damage, which has been attributed to metabolic activation of the piperazine ring which generates an aldehyde intermediate.(129) Ketoconazole (249) is also a potent human CYP3A4 inhibitor that can alter the serum levels of many drugs including macrolide antibiotics that are metabolized by CYP3A4, thus increasing the toxicity of these agents.(130) The CYP3A4 inhibition associated with 249 is attributed to the imidazole ring, which coordinates the Fe atom of the enzyme. Replacement with a triazole led to second-generation antifungal azoles including 250, which has shown a better safety profile and an expanded spectrum of activity, although potent CYP3A4 inhibition remains a problem.(128) The major site of metabolism of 249 is by N-deacetylation to afford 251 while for 250 it is oxidation to give hydroxyitraconazole 252.(131,132) Metabolite 253, which arises from dioxolane ring cleavage, was also detected in urine samples obtained from patients taking 250.(132b)
The discovery of 249 has its origins in a survey of analogues of miconazole (254), the first member of the conazole family, that was used primarily for the topical treatment of fungal infections.(133,136) The synthetic protocol under study employed 2-(imidazolyl)-acetophenone (255) as a starting material which was protected as the ethylene ketal 256 to facilitate further chemical transformations.(134) Surprisingly, the ketal intermediate 256 exhibited a broad-spectrum antifungal activity, an observation that prompted the synthesis of more complex dioxolanes that incorporated a substituent on the diol moiety. This exercise led to the discovery of 257, which cured C. albicans-infected animals in a rat model of vaginal candidiasis, and 258 and 259, which cured guinea pigs of a cutaneous C. albicans infection after oral doses of 10 mpk.(135) However, while none of these compounds were effective in both infection models, the incorporation of an oxygen atom in the side chain moiety resulted in the identification of the phenoxymethyl ketals 260 and 261, which demonstrated superior oral efficacy in effecting cures in both models of fungal infection.(136) Subsequently, a piperazine moiety was added to the side chain to improve both solubility and oral absorption, an effort that culminated in the discovery of 249.(127)
The biochemical target of 249 is the enzyme 14-α-sterol demethylase, a CYP450 monooxygenase of the CYP51 gene family that converts lanosterol to ergosterol, a constituent of fungal cell membranes.(131a) Docking studies of 249 within the active site of CYP51 suggested that there were no direct H-bonding interactions between the ketal oxygen atoms and the enzyme, but the cyclic ketal played an important role in orientating the imidazole group directly above the central heme iron atom with a distance of 3.458 Å between the sp2 nitrogen of the imidazole and the catalytic Fe atom.(137) In this bioactive conformation, the 2,4-dichlorophenyl ring engaged with the side chain of Phe134 via a π–π stacking interaction while His381 is able to donate a H-bond to the side chain oxygen atom of 249. In addition, the two ketal oxygen atoms of ketoconazole contribute to its favorable lipophilicity (cLogP = 3.6), which translated into superior oral absorption and oral bioavailability when compared to the more lipophilic 254 (cLogP = 5.8).
SB203580 (262) is a selective p38α mitogen-activated protein (MAP) kinase inhibitor explored for its potential to treat rheumatoid arthritis; however, this compound exhibited modest oral bioavailability, induced chromosomal damage, and inhibited CYP1A1.(1,138) To address these issues, the phenyl ring at the 2-position of the imidazole, which binds in the same region as adenosine triphosphate (ATP), was replaced with a cyclic acetal, leading to the identification of two compounds, 263 and 264, with good oral bioavailability and oral efficacy in a rat model of the streptococcal cell wall (SCW)-induced arthritis.(1,138) The synthetic protocol produced a mixture of isomers which were separated by chromatography and the identities of individual compounds assigned based on the assumption that the diarlyated imidazole would adopt an equatorial disposition on the dioxane ring. These acetal analogues were found to be highly resistant to acidic, basic, and oxidative conditions, which may be attributed to the mild basicity associated with the imidazole ring and/or the modest electron-withdrawing effects associated with the 2-position of the heterocycle, which would help to destabilize the positively charged intermediates that arise during hydrolysis.(139) This approach to stabilizing acetals and ketals, which has found only limited application in medicinal chemistry, was extended within this series of p38α MAP kinase inhibitors to include the azoles 265–268, which are advantageous based on their reduced lipophilicity and increased fraction of saturated carbon atoms (Fsp3) compared to the phenyl ring homologues.(47,140,141)
RP70676 (269) was identified as a potent orally bioavailable acyl-CoA:cholesterol O-acyltransferase (ACAT) inhibitor suitable for the treatment of atherosclerosis, but it underwent rapid metabolism to give two enantiomeric sulfoxides, of which only the (S)-(−)-isomer RP73163 (270) showed moderate ACAT inhibition while 271 was inactive.(142) This prompted a study directed toward replacing the sulfoxide linkage with a conformationally restrained group, preferably a heterocycle, which would maintain the imidazole and pyrazole elements in their bioactive conformation and enhance potency. As the first step in that process, a number of simple 2-substituted 4,5-diphenyl-1H-imidazole derivatives 272-276 were evaluated to determine the optimal minimal pharmacophore required to maintain inhibitory activity. This survey revealed that the preferred 2-substituents were the six-membered rings 1,3-dioxan-2-yl (272), tetrahydropyran-2-yl (274), and phenyl (276). However, the lipophilicity of 276 was a concern for solubility and oral absorption, while the tetrahydropyran-2-yl substituent in 274 introduces the complication of a chiral center which would mean that rapid SAR expansion would be a challenge. As a result, the 2-(1,3-dioxan-2-yl)-4,5-diphenyl-1H-imidazole moiety 272 was selected as the vehicle for further optimization because of its potent inhibitory activity, desirable lipophilicity, and facile synthetic accessibility. Chemical lability toward hydrolysis was judged to be of limited concern based on the presence of the moderately basic imidazole heterocycle. Both cis- and trans-disposed compounds were isolated, with 1H NMR data suggesting that the dioxane ring system adopted a chair conformation with the bulky 4,5-diphenyl imidazole moiety oriented equatorially.(142) The CH2 protons of the axial hydroxymethyl substituent of the cis-isomer 281a encountered 1,3-diaxial interactions with the lone pairs on the oxygen atoms, thus resonating downfield when compared with the trans-isomer 281b in which this group is equatorial (3.86 vs 3.41 ppm) (Figure 8). A similar downfield effect was observed with the methyl group of the trans-isomer (1.25 vs 0.8 ppm). In this example, the chair conformation of the dioxane ring system provides a useful scaffold on which to deploy substituents with good stereochemical control. The cis disposed 277 (IC50 = 75 nM) was more potent than the trans-isomer 278 (IC50 = > 500 nM). Further optimization led to the water-soluble compounds 279 (IC50 = 60 nM) and 280 (IC50 = 70 nM). When dosed orally at 10 mpk in rats, 279 and 280 produced plasma concentrations of 1.3 μM and 2.2 μM, respectively, at 90 min post dose, 20- and 30-fold higher than their IC50 values for ACAT inhibition in macrophages.(142) Both compounds were considered as potential candidates for development as oral therapeutics for the treatment of atherosclerosis.
Figure 8
Figure 8. 1H NMR data for the substituted dioxanes 281a/b.
Oxapadol (282) is a non-narcotic analgesic that demonstrated activity in models of pain conducted in mice, rats, and rabbits, providing the basis of advancement into clinical trials which occurred in the late 1970s.(143) SAR studies indicated that the dioxolane ring and its relationship and connectivity with the benzimidazole were of importance to the expression of pharmacological activity, which was assessed by screening for analgesic activity in mice as protection against phenylbenzoquinone-induced writhing.(143a) While 282 appears to have been advanced as a racemic mixture, the (1R,4S)-isomer 283 was more potent than the (1S,4R)-enantiomer 284 with ED50 values of 30 and 100 mpk, respectively. In a placebo-controlled trial conducted in 10 medical students, 282 was evaluated for its ability to attenuate the nociceptive reflex in the lower limbs in response to an electrically induced stimulus. Oral doses of 600, 800, and 1000 mg of 282 were associated with an increase in the nociceptive threshold at time points after drug ingestion ranging from 30 to 180 min, with the effect at all doses reaching statistical significance compared to placebo.(144a) Oxapadol (282) was extensively metabolized following oral dosing to rats, dogs, and humans with no unchanged drug detected rat and human urine and just trace amounts in dog urine.(144b) A total of nine metabolites were identified that reflected hydroxylation of the benzimidazole ring and cleavage of the dioxane-containing heterocycle moiety, with phenol metabolites dominant in humans and amounting to 40% of the radioactivity in urine while N-dealkylation to give 286 and 287 was observed in rats and dogs but not humans. Acid-mediated dioxolane hydrolysis in the gut was considered as a possible contributor to the fate of the molecule in vivo since incubation of 283 at pH = 2 and 37 °C resulted in slow hydrolysis to afford 285, one of the identified metabolites, although 93.5% of the parent remained after 120 min of incubation suggesting this pathway to be of low significance (Scheme 15).
Scheme 15
Scheme 15. Acid-Catalyzed Degradation of 282 to afford 285 and the N-Dealkylation Metabolic Pathway Observed in Rats and Dogs to Afford 286 and 287
Bicyclic Acetals and Ketals
Bicyclic acetal/ketal or hemiacetal/ketal motifs in which the oxygen atoms are in the same ring are ubiquitous in carbohydrates and natural products, and both topologies offer increased resistance to acid-mediated hydrolytic decomposition because the formation of the acetal or ketal is a fast and thermodynamically favored intramolecular process. Acetalizaton and ketalization of this type offer a straightforward and sometimes readily accessible approach to conferring conformational rigidity while introducing polarity, which can translate into enhanced biological and pharmaceutical properties.(145)
Bridged Acetals
Since O-glycosides like phlorizin (172) are limited by poor pharmacokinetic properties (vide supra), extensive study has been devoted to the development of analogues with improved metabolic stability and improved oral bioavailability, culminating in the discovery of canaglifozin (288) and dapagliflozin (289), C-aryl glucosides which were approved by the FDA in 2013 and 2014, respectively, for glycemic control in adults with type 2 diabetes.(146,147)
An overwhelming majority of the continued efforts on C-aryl glucosides have focused on the aglycone side chain due to the pharmacophoric requirements associated with the sugar ring and the relatively straightforward chemical transformations available to modify that element.(148) However, one modification to the glucoside moiety that has been examined is through a novel cyclization strategy that establishes a link between C1 and C5 using a CH2O bridge.(149) When this transformation was implemented in the background of 289, ertugliflozin (290) was identified as an SGLT2 inhibitor that displayed improved inhibitory activity and selectivity over SGLT1 (Figure 9).(149) This compound exhibited low plasma clearance in rats and dogs, with t1/2 values of 4.1 and 7.6 h, respectively, while oral bioavailability was 69% in rats and 94% in dogs. In humans, 290 exhibited 100% oral bioavailability and a terminal elimination t1/2 in the range of 11–18 h, which supported a QD dosing regimen.(150)In vitro biotransformation studies with 290 in liver microsomes and cryopreserved hepatocytes from rats, dogs, and humans revealed no evidence of ketal cleavage.(150a) The discovery of 290 is an interesting example of the role of innovative chemistry as an integral part of modern drug discovery, further illustrated by the observation that the alternate 1,5-linker topology in iso-ertugliflozin (291) affords a compound that is over 800-fold less potent.(149,151)
Figure 9
Figure 9. Design principles that led to the discovery of 290.
More recently, this 1,5-cyclization strategy has been extended to the thiomethyl xyloside core of sotagliflozin (292), a dual SGLT1 and SGLT2 inhibitor that is approved in Europe for the treatment of type 1 diabetes mellitus.(152) In this case, cyclization to give 293 reduced the SGLT2 potency by nearly 10-fold, but replacing the thiomethyl substituent with a methoxy afforded HSK0935 (294), which restored SGLT2 inhibitory potency while simultaneously increasing selectivity over SGLT1 inhibition.(153) Overall, in this context 1,5-cyclization of 292 transformed a dual inhibitor into a selective SGLT2 inhibitor, and 294 is currently undergoing preclinical development for the treatment of type 2 diabetes.
The enzyme 5-lipoxygenase (5-LO) enzyme metabolizes arachidonic acid and plays an important role in the production of leukotrienes which cause inflammation in asthma, allergic rhinitis, and osteoarthritis, providing the basis for interest in the discovery of 5-LO inhibitors as antiinflammatory agents.(154) L-702,539 (295), a tertiary alcohol derivative, was identified as a selective and moderately potent 5-LO inhibitor but was the subject of extensive oxidative metabolism, with 296–299 identified as inactive metabolites that amounted to 6–7% after 1 h incubation in RLM (Figure 10).(155a) The two major metabolic soft spots were the lactone and the tetrahydropyran ring, with the former affording the hydroxylactone 296 while the latter generated the hydroxypyran 297, which was further oxidized to the hydroxy acid 298, a metabolite also in equilibrium with lactone 299 (Figure 10). To block α-hydroxylation on the tetrahydropyran ring, both positions were substituted with a bridging moiety that created the oxabicyclooctane analogue 300, a compound associated with fewer metabolites than the prototype in the plasma following oral dose to rats. However, 300 was 3-fold less potent than 295 in both a human 5-LO and a human peripheral blood polymorphonuclear monocyte (HPMN) assay and 7-fold less active in a human whole blood (HWB) assay, which was attributed to the increased protein binding due to higher lipophilicity (cLogP = 4.8 for 300 compared to 4.3 for 295). Transformation of the oxabicyclooctane core in 300 into a dioxabicyclooctane homologue 301 reduced the cLogP from 4.8 to 4.1, which translated into a 2-fold enhancement in potency in the HWB assay (IC50 = 540 nM compared to 1 μM for 300). More importantly, incorporation of the second oxygen atom in the ring to form a cyclic acetal led to improved metabolic stability with only 1–2% of the molecule metabolized by RLM over 1 h of incubation. Thus, the dioxabicyclooctane bicyclic ring system was established as a metabolically stable surrogate of a tetrahydropyran ring, and 301 was subjected to additional optimization by phenyl ring modification which identified the 3-furyl analogue 302 as a compound comparable to 295 in both the human 5-LO and HWB assays. After oral administration of 302 to rats, no major metabolites were detected with the exception of the expected hydroxylactone. Hydroxylative metabolism of the lactone moiety was addressed by replacement with a nitrile which furnished 303, a compound that generated only a single metabolite in RLM that amounted to just 0.4% of material after 1 h of incubation. The strong resilience to oxidative metabolism was also demonstrated in vivo with no major metabolites observed after oral studies in rats at a dose of 20 mpk.(155a) Nevertheless, further development of 303 was hampered by moderate potency and low oral bioavailability (10% in rats) due to limited oral absorption, which was ascribed to its high lipophilicity (cLogP = 4.1). Adding a nitrogen atom to the phenyl ring to provide the pyridine homologue 304 resulted in a 1.4 unit reduction in the cLogP value, which translated into a 2.5-fold increase in oral bioavailability in rats and a 2-fold improvement in Cmax in rat plasma (5 μM compared to 2.5 μM for 303, 20 mpk, PO).(155b) In contrast, the tetrahydropyran prototype 307 exhibited a much lower Cmax (2 μM), again demonstrating the potential of using the dioxabicyclooctane ring as a metabolically more stable bioisostere of tetrahydropyran. L739,010 (304) also presented a favorable pharmacokinetic profile in dogs with an oral bioavailability of 73% and an estimated half-life of 16 h. The pyridine analogue 304 was also significantly more active than the phenyl analogue 303 with HWB an IC50 of 42 nM and elicited robust oral efficacy in several animal models of asthma including a functional model of antigen-induced bronchoconstriction in allergic squirrel monkeys. However, biotransformation studies in rat, dog, monkey, and human liver microsomes revealed oxidative cleavage of the furan moiety to the highly reactive 2-butene-1,4-dialdehyde derivative 305 as the major site of metabolism while hydroxylation of the unsubstituted dioxabicyclo moiety to give 306 was a minor pathway.(156) Development of 304 was discontinued presumably because of concerns associated with the metabolism of the furan ring into products capable of effecting covalent binding in vivo.(156)
Figure 10
Figure 10. Structure of the 5-LO inhibitor 295, metabolic pathways and structural evolution.
Spiroketals
A spiroketal core emerged as a design element that enforced the nearly perpendicular orientation between the glucoside and proximal phenyl of the aglycone observed in the lowest energy conformation of several SGLT2 inhibitors.(157) This spiro scaffold originated from the hit compound 309 that was identified from a search of the Cambridge Structural Database (CSD) in which a glucose core with two pendent aromatic rings, Ar-1 and Ar-2, was used as the pharmacophoric elements that were derived from an overlay of four SGLT2 inhibitors with the in-house C-naphthyl glucoside inhibitor 308 (Figure 11). An absence of promising lead structures necessitated an adjustment to the query, which relaxed the search to two pharmacophore elements, the glucose moiety and Ar-1 (Figure 11). This pharmacophore enquiry identified 309 as a molecule with promising structural overlap with prototype SGLT2 inhibitors notably 310, the core of dapagliflozin (289). Substitution of the 1,3-dihydroisobenzofuran in a fashion designed to mimic known SGLT2 inhibitors afforded 311 and 312 as representatives of a new C-aryl glucoside class of potent SGLT2 inhibitors. Analogues lacking the chloro substituent on the central phenyl ring exhibited superior potency and selectivity, with the 4-ethyl benzyl derivative tofogliflozin (314) superior to the 4-ethoxybenzyl homologue 313. Interestingly, the chlorinated compound 312 caused severe diarrhea in mice 6 h after a single oral dose of 25 mpk; however, the des-chloro counterpart 314 posed no toxicity issues.(158) When compared with 289, 314 showed comparable SGLT2 inhibitory activity with enhanced SGLT1 selectivity, as well as excellent oral bioavailability in mice (75%), cynomolgus monkeys (85%), and humans (98%).(157)
Figure 11
Figure 11. Design principle subtending the discovery of the core bicyclic ring system found in tofogliflozin (314).
The spirocyclic ketal 1,7-dioxaspiro[5.5]undecane 315 was designed as a conformationally restricted template to secure the disposition of the two key aromatic rings required for potent inhibition in a series of NK1 antagonists (Figure 12).(159a) The spiroacetal system in 315 exists exclusively in conformation 315a due to the anomeric effects, which are additively reinforcing since both C–O bonds in the spiro ring system are antiperiplanar to an oxygen lone pair, and 315 can thus be considered as a conformationally biased system. In terms of free energy, 315a is 2.27 kcal/mol lower than 315b, which benefits from only a single anomeric effect, and 4.54 kcal/mol lower than 315c. Based on molecular modeling, the (5S,6S,9S)-isomer of 315 offered the optimal orientation of the two aryl rings critical for recognition by the NK1 receptor while also providing the potential for a key hydrogen-bonding interaction between the oxygen atom at the 7-position and the receptor. Indeed, 316 (hNK1 IC50 = 28 nM) was significantly more potent than the (5S,6S,9R)- (44% inhibition at 1 μM), (5S,6R,9S)- (47% inhibition at 1 μM), and (5S,6R,9R)- (hNK1 IC50 = 400 nM) diastereomers (structures not explicitly shown). Optimization of 316 afforded 317 and 318, both of which demonstrated very high NK1 binding affinity and good CNS penetration, as measured by blockade of agonist-induced foot tapping in the gerbil following an IV dose.(159a) The [4.5]-spiroacetal analogue 319 exhibited hNK1 inhibitory potency comparable to 316, which was refined to 320, a potent hNK1 antagonist with good CNS penetration following IV dosing. However, the chemical stability and oral bioavailability of this series of NK1 antagonists were not described. The potential of this interesting spiroacetal scaffold remains to be further explored since this article is the only description of its application in structure-based drug design, although there are extensive studies on spiroacetal-based natural products with similar motifs.(159b−e)
Figure 12
Figure 12. Conformations available to 1,7-dioxaspiro[5.5]undecane (315).
Bis-THF and Tris-THF Moieties in HIV-1 Protease Inhibitors
A series of human immunodeficiency virus-1 (HIV-1) protease inhibitors incorporating a bis-tetrahydrofuran (bis-THF) as the P2 element was designed based on the X-ray cocrystal structure of saquinavir (321) bound to the enzyme, which revealed critical H-bonds between the P2-asparagine carbonyl and the backbone NH of Asp30 and the P3-quinaldic amide carbonyl and the backbone NH of Asp29 (Figure 13).(160) In the designed bis-THF ligand 322, both acetal oxygen atoms are optimally deployed to function as H-bond acceptors by simultaneously engaging the backbone NH’s of Asp30 and Asp29. The bicyclic acetal functionality is key for potent protease inhibitory activity since the two mono-THF analogues 323 and 324 are significantly less active, presumably a function of the loss of one of the H-bonding interactions. The bis-THF P2 moiety derivative possesses a lower molecular weight, fewer amide bonds, and reduced lipophilicity compared to 321, all of which contribute to improvements in solubility and oral bioavailability. Deploying the bis-THF P2 moiety on the structural background of amprenavir (325) led to the discovery of darunavir (326) as a conceptually new HIV-1 protease inhibitor with high potency and clinical efficacy toward resistant viral infections.(160) In this context, the bis-THF ring system mimics aspects of the sulfone moiety of 327 but with the advantage that the topographical disposition of the O atoms is such that it can engage both HIV-1 protease H-bond donors. Darunavir (326) is extensively metabolized almost exclusively by CYP3A4, and coadministration with small doses of the potent CYP3A4 inhibitor ritonavir increases its oral bioavailability from 37% to 82% in humans, although the dosing combination had a more modest effect on the PK profile in mice (2-fold), rats (4-fold), and dogs (no effect).(161) The major metabolites of 326 reflect carbamate cleavage, hydroxylation of the iso-butyl moiety, hydroxylation of the aniline ring, and small amounts of benzylic hydroxylation to afford an alcohol that is glucuronidated.(161) The bis-THF ring of 326 does not appear to be a site of metabolic modification, unlike in the progenitor 325, where dihydroxylation of the THF ring followed by ring opening was found to be a major metabolic pathway.(162) Darunavir (326) was approved by the FDA in 2006 for the treatment of HIV-1 infection and acquired immunodeficiency syndrome (AIDS), and it is on the WHO’s List of Essential Medicines.
Figure 13
Figure 13. Structure of HIV-1 protease inhibitor 321 depicting key intermolecular H-bonding interactions and evolution to bicyclic ethers.
Peroxy Ketals (R–O–O–C–O–R′)
1,2,4-Trioxanes
The discovery of artemisinin (195) as a malaria therapy by over 500 scientists from 60 institutions across China in the 1970s represented one of the greatest advances in medicine in the 20th century.(164) Artemisinin (195), also known as qinghaosu, was isolated from leaves of the Chinese plant Artemisia annua (qinghao or sweet wormwood) and possesses an unprecedented structure that combines a sesquiterpene lactone with an embedded cyclic peroxy ketal and an acetal. Surprisingly and perhaps remarkably considering the structure, 195 exhibits unusual stability toward both heat and light. No appreciable decomposition occurs when 195 is heated at 150 °C in neutral solvents, which is just below its melting point of 156–157 °C, and the compound can be sublimed, while the neat solid survives heating at 200 °C, 50 °C above its melting point, for 2.5 min.(165) The unusual stability of the peroxide moiety in 195 has been attributed to the adjacent acetal functionality, which is believed to benefit from a stabilizing interaction between the antiperiplanar lone pair of the peroxide oxygen and the σ* orbital of the pseudo axial acetal C–O bond which has been attributed to hyperconjugation or an anomeric effect (Figure 14). According to natural bond orbital (NBO) calculations, this anomeric interaction is worth 17.0 kcal/mol, a strong stabilization due to the enhanced donor ability of the peroxide oxygen lone pairs that is based on the α-effect.(166)
Figure 14
Figure 14. Depiction of the anomeric effect in 195.
The cyclic peroxy ketal of 195 is an essential element of the pharmacophore in the expression of antimalarial activity. For example, the desoxy compounds 330 and 330a, which lack the peroxide bridge, are devoid of antimalarial activity, while replacing one of the peroxide oxygen atoms with methylene (331) also diminishes inhibitory activity; however, the 10-deoxo compound 332, which retains a peroxide group, is even more active than 195.(167) The expression of antimalarial activity by 195 depends upon activation of the peroxy moiety although the precise mechanism of bioactivation remains under debate. A carbon radical pathway which postulates that binding of the ferrous heme/nonheme exogenous Fe2+ to the peroxide bridge is followed by electron transfer to induce reductive scission of the peroxide bond, thereby producing oxygen-centered radicals 333 and 335, which rearrange to carbon-centered radicals 334 and 336 is one of the prevailing hypotheses (Scheme 16).(168a−c) The carbon-based radicals 334 and 336 are believed to react with parasite proteins that mediate critical biochemical pathways, thereby killing the organism.(168d)
Scheme 16
Scheme 16. Potential Modes of Action of 195 Relying upon Iron-Catalyzed Degradation to Oxygen- or Carbon-Based Radicals
The poor solubility of 195 in both water and lipid has provided an impetus to identify semisynthetic analogues with improved solubility and pharmaceutical properties.(103,105,169) Toward this end, the carbonyl group of 195 was reduced with NaBH4 to give 196, which was converted into a series of acetals that included the lipid-soluble artemether (202) and arteether (337) and the water-soluble artelinic acid (338) and 339 as well as artesunate (340), which also showed enhanced antimalarial activity.(169) Artemether (202), which can be taken orally, is the most prescribed analogue, while artesunate (340) is preferred for IV administration due to its high aqueous solubility. After oral administration, 202 and 340, but not 195, are rapidly biotransformed to DHA (196), the major active metabolite, primarily by CYP2B6 in the liver. Artemisinins kill malaria parasites within minutes, resulting in a rapid clinical response; however, they are limited by short half-lives. Therefore, artemisinin combination therapies are desirable for the first-line treatment of P. falciparum malaria as the artemisinin kills most parasites at the beginning of the therapy, while the other long-lasting drug eradicates the remaining parasites.(103)
The poor oral bioavailability associated with artemisinins has been ascribed to the hydrolytic instability of the acetal-lactone or acetal–acetal moieties. The stability of artemisinin analogues has been evaluated in simulated stomach acid (0.01 N HCl, pH 2.0 at 37 °C).(170) The disappearance half-lives ranged from 11 to 24 h, with the stability in the following order: 195 (24 h) > 196 (17 h) > 339 (13 h) > 338 (11 h). To improve the acid stability of artemisinin analogues, a series of nonacetal-based analogues containing a C–C bond at C10, as exemplified by 341-346, was prepared.(171) These compounds showed remarkable acid stability with disappearance t1/2 values ranging from 165 to 259 h in 0.01 N HCl, pH 2.0 and 37 °C. The non-acetal-based analogues 341–343 possessed sufficient stability in simulated stomach acid to be suitable for oral administration, while 345 and 346 had sufficient stability and aqueous solubility to possess the shelf life required for an IV-administered formulation. The in vitro antimalarial activities of 341–346 were either comparable to or superior to their acetal counterparts. Deoxoartelinic acid (346) also showed higher in vivo suppression toward Plasmodium chabaudi-infected mice than 202.(171)
Conversion of 195 to its 11-aza derivatives provides another approach to improve oral bioavailability.(164c,172) These azaartemisinins displayed a better antimalarial activity profile than that of 195. For example, oral administration of the amino- and hydroxy-functionalized 11-azaartemisinins 347 and 348 elicited robust antimalarial activity against multidrug-resistant Plasmodium yoelii in rodents. A series of 10-alkylaminoartemisinins that included artemisone (349) and artemiside (350) and exhibited improved aqueous solubility, enhanced metabolic stability, and higher oral activity, compared to artemisinins, have also been developed.(173) Notably, 349 was not susceptible to metabolic cleavage of the C–N bond to give 196, a compound believed to be a source of neurotoxicity associated with artimisnins in some patients.
Artimisinin derivatives remain the most potent and fast-acting antimalarial agents, but they are still limited by short half-lives in vivo, high cost of goods, and reliable supply issues. Every year, more than 100 tons of artimisinin are used to produce semisynthetic analogues, and the only practical way to access it is still through extraction from the plant. This has stimulated effort directed toward the development of fully synthetic, peroxide-containing drugs designed to present the pharmacophoric 1,2,4-trioxane moiety. Toward this end, the fully synthetic trioxanes 351 and 352 were prepared to allow comparison with their respective trioxolane counterparts, arterolane (353) and artefenomel (354).(174) The oral exposure of compound 351 was 4-fold higher than that of 353, but its overall antimalarial efficacy was not improved due to its lower intrinsic antimalarial potency. Trioxane 352 exhibited similar potency to 354, but its antimalarial efficacy was inferior due to its lower exposure following oral administration.(174)
Hybrid trioxaquines that combine a 1,2,4-trioxane with the 4-aminoquinoline moiety of antimalarial agent chloroquine (355) have been synthesized in an effort to develop molecules with a dual-mode of action that combines heme alkylation by the trioxane moiety with heme stacking by the aminoquinoline heterocycle to inhibit hemozoin formation.(175a,b) One of the early analogues, DU1302 (356), was potently efficacious following oral administration in a mouse model of malaria, but its structural complexity due to the presence of two chiral centers was a concern for further development.(175a) Subsequently, the simplified trioxaquine PA1103/SAR116242 (357), which is devoid of any chiral centers, was selected for development from a series of 120 active analogues. This compound was highly active in vitro toward several sensitive and resistant strains of Plasmodium falciparum and exhibited good oral bioavailability in rats. In mice infected with chloroquine-sensitive or chloroquine-resistant strains of Plasmodia falciparum, low orally administered doses of 357 affected complete cures.(175b)
In addition to their antimalarial activity, artemisinin analogues have also been shown to have the potential for the treatment of cancer since the free radicals derived from the endoperoxide moiety following the encounter with iron can mediate cellular damage and initiate apoptosis in cells with high levels of iron.(175c) In general, artemisinin-derived dimers show higher antitumor activity than the more conventional monomeric artimisinin analogues.(175d) For example, dimer 358, IC50 = 43 nM, exhibited 8-fold enhanced potency in killing MTLn3 breast cancer cells in vitro compared to 196, IC50 = 360 nM, which translated into superior in vivo efficacy in suppressing the growth of MTLn3 tumors.(175d,e) The dimeric trioxane diphenylphosphate 359 was 88-fold more potent than 340 toward 23 human AML and acute lymphocytic leukemia (ALL) cell lines tested and interacted synergistically with sorafenib and venetoclax toward human acute leukemia cells in vitro and AML xenografts and primagrafts in vivo when tested in combination, collectively indicating the potential of the three drug combination as a therapy for AML and ALL.(175f) Mechanism of action studies in diffuse large B-cell lymphoma cells with the dimeric SM1044 (360) indicate that the antitumor effects involve the induction of autophagy and autophagy-dependent apoptosis.(175g) These dimers also offer advantages over monomers in terms of aqueous solubility and chemical stability.(175g)
Dispiro-1,2,4-trioxolanes
The development of a totally synthetic ozonide antimalarial with a quick onset of action, good oral bioavailability, and a single-dose regimen has been explored extensively.(164c,d,176) The first two dispiro-1,2,4-trioxolanes prepared and evaluated, 361 and 362, lacked antimalarial activity, suggesting that the peroxide bond was either too exposed or too sterically hindered to effectively interact with the heme iron(II). Trioxolanes 363 and 364, hybrids of 361 and 362 that take advantage of the low steric hindrance associated with one peroxide oxygen atom, which is thus more capable of accessing the iron(II) species, are active antimalarial agents. However, despite their potent in vitro and in vivo activity, both compounds possessed poor aqueous solubility (<1 μg/mL) and low oral bioavailability (<1% in rats), attributed to the high lipophilicity of the spiroadamantane trioxolane pharmacophore. Incorporation of an amine-containing acetamide side chain onto the cyclohexyl ring of 363/364, designed to reduce lipophilicity, afforded 353, which exhibited improved aqueous solubility and enhanced oral bioavailability in rats (F = 35%). In 2012, 353 was approved in India for the treatment for uncomplicated malaria infection as a fixed-dose combination with piperaquine administered in three doses on consecutive days.(176d)
Effort toward the development of second-generation ozonides has focused on improving the pharmacokinetic properties of 353 as a means of achieving a single-dose cure.(176c,d) Arterolane (353) has a relatively short half-life of 3 h in humans due to CYP3A4-mediated hydroxylation of the adamantane ring, which produces inactive metabolites, and decomposition catalyzed by Fe (II) in blood to give adamantane lactone and cyclohexanone as the cleavage products. Replacing the alkyl cyclohexyl moiety with an aryl cyclohexyl homologue ameliorated metabolic instability and also increased the stability in blood toward Fe (II) without compromising antimalarial efficacy. Final optimization of the aryl substituents afforded the highly potent and longer-acting 354, which offers the potential for a single-dose cure of uncomplicated malaria infection.(176d,e) This compound exhibited a half-life of greater than 20 h following oral dosing to rats, which compared to 1 h for 353 and 0.5 h for dihydroartimisinin (196), and an oral bioavailability of 76%, which compared to 35% for 353. In humans, 354 demonstrated an extended half-life of 46–60 h, which is essential for a single dose therapeutic schedule. Artefenomel (354) is currently in phase II clinical trials.(176d,e)
Dispiro-1,2,4,5-tetraoxanes
Compared to 1,2,4-trioxolane (365) and 1,2,4-trioxane (361), tetraoxane (366) is devoid of chiral centers and displays greater inherent thermodynamic stability, which has been rationalized in terms of a stereoelectronic “double anomeric effect” based on theoretical calculations (Figure 15).(166a) Tetraoxanes (367) also exhibit remarkable stability toward both strongly acidic (pH 1.6, MeOH/HCl, 37 °C) and basic (pH 12, NaOH/i-PrOH/H2O) conditions as well as harsh metal hydride reduction protocols, including exposure to LiAlH4.(177)
Figure 15
Figure 15. Depiction of the anomeric effects in 1,2,4-trioxolane 365, 1,2,4-troxane 361, and tetraoxane 366.
Potent antimalarial agents have been prepared based on the 1,2,4,5-tetraoxane scaffold 366.(178) While the unstable dispiro-1,2,4-trioxolane 365 lacked antimalarial activity in vitro, the tetraoxane homologue 366 is a potent antimalarial agent. As observed in the ozonide series, the fusion of the 1,2,4-trioxolane ring system to an adamantane core further enhanced chemical stability. Optimization of the side chain in the generic structure 367 in a fashion designed to counterbalance the lipophilicity of the adamantane moiety delivered RKA182 (368), formulated as the ditosylate salt, which demonstrated oral bioavailability in rats (38%) and mice (42%).(178b) Given its superior in vitro and in vivo activity compared to the artemisinins coupled with good oral bioavailability in rodent models, 368 was selected as a drug-development candidate.
However, 368 is associated with a relatively short 2.4 h half-life in rats following a single oral dose of 10 mpk, directing second-generation discovery toward overcoming the potential metabolic liability associated with amide-linked analogues.(178b) Following developments in the ozonide series, the amide side chain was replaced with a phenyl ring designed to improve metabolic stability, and a basic 4-fluoropiperidinylethyl moiety was incorporated as a phenyl substituent designed to reduce lipophilicity. This resulted in the identification of E209 (369) which exhibits good oral bioavailability across the species (62% in rats; 82% in mice; 40% in dogs). Allometric scaling using rat PK data predicted a terminal half-life of 24–30 h in humans (compared to half-lives of 1–2 h for currently available artemisinins) and an oral bioavailability of 62%, compatible with a single-dose cure, administered either as monotherapy or in combination.(178c,d)
The fully synthetic tetraoxanes 370 and 371 were also prepared for comparison with their respective trioxolane counterparts, 353 and 354.(174) Compound 370 showed comparable antimalarial oral efficacy to 353 despite similar in vitro activity and higher exposure in vivo. Compound 371 showed similar in vitro antimalarial activity to 354, but its oral activity was significantly reduced due to much lower exposure in vivo.
(N,O)-Aminals (R–N–C–O–R′)
In the absence of stabilizing group(s) designed to blunt amine basicity, simple (N,O)-aminals are generally less stable than their analogous acetals and ketals because protonation of the basic nitrogen atom is facile, which facilitates departure as a leaving group, resulting in significant sensitivity to hydrolytic degradation.(179a) However, there are circumstances where this kind of chemical reactivity can be beneficial, as exemplified by the antibiotic dirithromycin (372), which is a (9-N, 11-O)-aminal prodrug of 9(S)-erythromycyclamine (373) derived by conjugation with 2-(2-methoxyethoxy)acetaldehyde (374). The prodrug element is unstable under both acidic and neutral conditions and undergoes spontaneous, nonenzymatic degradation during absorption and in plasma to release the active macrolide antibiotic, thereby improving oral bioavailability (Scheme 17).(179) Following IV administration, conversion of 372 to 373 was complete within 1.5 h, with 60–90% conversion occurring during the first 35 min. In order to minimize acid-mediated degradation in the stomach, the prodrug 372 is formulated as enteric-coated tablets. Interestingly, despite being a prodrug, 372 is a more potent inhibitor of bacterial protein synthesis in vitro than 373, and the compound has been shown to bind to a complex of the 70S ribosome from Thermus thermophile and E. coli(180) In the X-ray cocrystal structure of 372 with the 70S ribosome from Thermus thermophile, one of the lone pairs of electrons on the oxygen atom of the prodrug moiety that is distal to the core of the molecule engages in a π-interaction with a His residue in the ribosomal protein uL4.(180)
Scheme 17
Scheme 17. Degradation of 372–373 and Aldehyde 374
The degradation rate of (N,O)-aminals largely depends on the nature of the substituents on both C2 and the nitrogen atom. The stability of aminals derived from carbonyl compounds follows the order: formaldehyde > alkyl aldehyde > ketone, a trend that parallels the respective acetals and ketals and is related to the ability to stabilize the developing carboxonium (carbonylonium) intermediate (Scheme 18). For example, the 2,2-dimethyloxazolidine-based dipeptides 375 hydrolyzed rapidly in dilute trifluoroacetic acid (TFA) to give 377 or 378, while, in contrast, the unsubstituted oxazolidines 376 proved to be exceptionally stable, and much longer reaction times in the presence of stronger acids such as trifluoromethanesulfonic acid (TfOH) were required to induce ring opening to give 377 or 378 (Figure 16).(181a) Analogous to acetals and ketals, aminals with electron-withdrawing groups at C-2 can be resilient toward acidic hydrolysis, as exemplified by the CF3- and CF2H-substituted pseudoprolines 379 and 380, which remained intact upon exposure to TFA in CDCl3 or H2O for 4–72 h at room temperature.(181b,c) As might be anticipated, the N-acetyl group also contributes to the stability of these molecules since the free NH pseudoproline 381 epimerizes in the presence of BF3•OEt2 to give a mixture of 381 and 382 while its N-acylated homologue 383 is stable under these conditions with none of 384 detected. In addition to enhancing chemical stability, the CF3 and CF2H substituents increase the preference for a cis-amide bond orientation in 386 due to steric interference in the trans-topology 385, while the cis-topology of the CHF2-substituted pseudoproline 387 is further favored, attributed to the formation of a stabilizing H-bond between the CF2H hydrogen atom and the amide carbonyl.(181c) These hydrolytically stable pseudoproline derivatives may be useful in drug design but have yet to be gainfully exploited.(181d)
Scheme 18
Scheme 18. Mechanism of Acid-Catalyzed (N,O)-Aminal Hydrolysis
Figure 16
Figure 16. Structures and chemical stability under acidic conditions of pseudoproline derivatives.
A series of aminal-linked tetracyclic inhibitors of the HCV NS5A replication complex derived from the benzofuran prototype MK-4882 (388) has been developed in which a poorly basic indole nitrogen atom is part of the geminal diheteroatomic motif, as exemplified by 390 (Figure 17).(182) In order to improve the antiviral activities of 388 toward clinically relevant HCV GTs and resistance mutations, the benzofuran core was converted to an indole scaffold. This molecular edit allowed the introduction of a bridge between the indole nitrogen atom and C5 carbon of the proximal phenyl ring through either an ethylene (389) or an oxygen-containing linker (390) that enabled substitution in a region of the pharmacophore known to be tolerant. The tetracyclic indole derivatives 389 and 390 displayed comparable activity to 388 toward GT-1a and GT-1b HCV WT replicon systems although, interestingly, the ethylene analogue 389 showed reduced activity toward the GT-1a Y93H mutant (EC50 = 170 nM) that can arise as the result of selective resistance pressure from first-generation HCV NS5A inhibitors. However, the introduction of the oxygen atom in 390 improved the GT-1a Y93H inhibitory activity by 34-fold (GT-1a Y93H EC50 = 5 nM). While the aminal linkage in 390 was shown to be extremely stable toward hydrolytic cleavage, even under forcing conditions, the compound exhibited cytotoxicity in the low μM range (CC50 ≈ 1 μM). Fortunately, the toxicity could be circumvented by adding a phenyl substituent at the aminal carbon atom (C6), and one of the two resulting diastereomers, elbasvir (391, MK-8742), was on average an order of magnitude more potent than 388 toward most of the HCV NS5A mutations evaluated. Elbasvir (391) was metabolically stable in liver microsomal preparations obtained from rats, rabbits, dogs, and humans and in mouse, rat, dog, and human hepatocytes, but its oral bioavailability was still in the low to moderate range (9% in rats; 35% in dogs; 17% in monkeys), which can be attributed to its limited oral absorption, as suggested by its low passive permeability.(182e) Elbasvir (391) is marketed in combination with an HCV NS3/4A protease inhibitor under the trade name Zepatier as a once-daily oral treatment option for chronic HCV GT-1 and GT-4 infections.
Figure 17
Figure 17. Structures and evolution of HCV NS5A inhibitors.
Further study within this series was directed toward developing an inhibitor with potent activity against all genotypes and a minimal potency shift (∼10-fold) between the wild-type virus and clinically relevant polymorphisms. These efforts led to the discovery of ruzasvir (MK-8408, 392) as a potent, pan-genotype HCV NS5A inhibitor with optimized activity toward common resistance-associated polymorphisms.(182c,d) The fluorine substituent in 392 contributed to a significant improvement in GT-1a Y93H potency. Similar to 391, 392 showed low to moderate oral bioavailability in rats (5%) and monkeys (10%); however, combination trials with 392 were discontinued after phase II clinical trials for business reasons.
Clavulanic acid (393) is a naturally occurring β-lactam derivative in which an acylated hemiaminal is embedded at the fused ring junction, a strained structural element that is integral to its biological activity.(183) Clavulanic acid (393) has little intrinsic antibacterial activity but is a mechanism-based inhibitor of serine-based β-lactamases; consequently, it is typically combined with penicillin-type antibiotics to overcome resistance by preventing β-lactamase-mediated degradation of the antibiotic, thus enhancing their effectiveness toward bacteria that express these enzymes.(183) The proposed mode of β-lactamase inhibition by clavulanic acid is presented in Scheme 19 and, while complex, relies upon the intrinsic reactivity of the embedded N–C–O moiety that is unmasked by the enzyme after deacylation of the oxazolidine nitrogen atom. Cleavage of the β-lactam ring of 393 as the result of an attack by the catalytic serine-70 (Ser70) of the β-lactamase relieves the stabilizing constraint on the N–C–O element, releasing the oxazolidine ring to give 394, which readily opens to generate an imine intermediate 395 that is poised to engage in several pathways of reactivity.(184) Tautomerism to the enamino ester 398 would reduce the susceptibility of the ester moiety toward hydrolysis while decarboxylation of imine 395 to give 399 followed by tautomerism to the enamino ester 400 has also been observed. Fragmentation of the imine 395 by hydrolysis releases (R)-2-amino-5-hydroxy-3-oxopentanoic acid (397), leaving an enzyme acylated by 3-oxopropanoic acid (396). Trapping of the imine 395 by Ser130 of the enzyme to generate a cross-linked, irreversibly inhibited enzyme has also been proposed with the elimination of 397 to give an alkoxyacrylate 402 via 401.(184) Clavulanic acid (393) is maximally stable at pH values between 5.8 and 6.5, with degradation in alkaline solutions proceeding approximately 8-fold faster than in acidic media, while comparison with penicillin G indicates a 10-fold faster degradation at neutral pH and a 5-fold faster rate at high pH while acid stability is comparable.(185) The acid- and base-promoted decomposition of clavulanic acid presumably involves β-lactam ring cleavage and/or opening of the oxapenam ring.(185) Clavulanic acid exhibits high oral bioavailability (70–97%) when administered alone with 20 to 60% of the drug excreted in the urine unchanged, but varied from 31% to 98% when coadministered with amoxicillin, suggestive of a DDI.(186)
Scheme 19
Scheme 19. Proposed Mechanism of Inactivation of Serine-Containing β-Lactamase Enzymes by 393
Rezafungin (CD101, 404) is an interesting antifungal agent derived from anidulafungin (403) in which the acylated and alkylated hemiaminal is further stabilized by the pendent positively charged choline ether moiety (Figure 18).(187) This macrocyclic peptide is a semisynthetic derivative of the echinocandin class that inhibits fungal cell wall synthesis, a mechanistic phenotype that has led to them being referred to as the “penicillins of antifungals”.(188) However, the chemical instability and poor solubility associated with echinocandins impose serious limitations for manufacturing, storage, and the development of suitable dosage forms. Chemical decomposition is initiated by the facile cleavage of the acylated hemiaminal in 403, which occurs in both plasma and buffered solutions. In contrast, 404 showed no appreciable degradation in PBS buffer and was quite stable in plasma from rats, dogs, monkeys, and humans with 9%, 21%, 6%, and 7% degradation occurring over 44 h, respectively. The ring-opening step that initiates the chemical degradation results in a carboxonium (carbonylonium) intermediate that, in the case of 404, is disfavored due to the presence of the proximal quaternary ammonium substituent, reflecting the generation of a repulsive and destabilizing interaction between the dual positive charges (Figure 18). The absence of a significant amount of both the acyclic aldehyde intermediate and GSH adducts also suggested the potential for reduced toxicity.(187b) The positively charged choline ether also greatly enhanced aqueous solubility. Given its exceptional stability and good solubility, 404 is undergoing phase III clinical evaluation as a once-weekly IV formulation for the prevention and treatment of invasive fungal infections.(187,188)
Figure 18
Figure 18. Structures and degradation pathways of 403 and 404.
An acylated cyclic hemiaminal ether moiety is a prominent structural feature of the HIV-1 integrase inhibitor dolutegravir (407) (Figure 19).(189) A hydroxyl substituent was introduced to the saturated piperazinone ring of the lead compound 405 to improve potency toward a key clinically relevant integrase mutant, but the hemiaminal functionality posed concerns for chemical stability. This was addressed effectively by annealing it with the adjacent methyl group to form a tricyclic analogue which produced two enantiomers 406a and 406b that were resolved and evaluated in pure form with no interconversion or chemical stability issues observed. Both enantiomers wereequipotent and displayed good oral bioavailability; however, an enantioselective synthesis was not readily available, and resolution of the racemate was not an option for production in terms of cost of goods. Fortunately, when the enantiomerically pure α-methylamino alcohol 409 was used in the formation of these cyclic aminals from 408, a 20:1 diastereoselectivity was observed, and 410 was isolated in 81% yield after single recrystallization (Figure 19). Hydrogenation gave 407, which was comparable to the unsubstituted enantiomers 406a and 406b. In this case, the synthesis methodology played an important role in selecting candidates for further development, and 407 was approved for the treatment of HIV-1/AIDS in the United States in 2013 and is on the WHO’s List of Essential Medicines.
Figure 19
Figure 19. Principle behind the design and synthesis of the HIV-1 integrase inhibitor 407.
The HIV-1 integrase inhibitor bictegravir (411) retains elements of the metal-binding pharmacophore of 407 but combines a bridging element installed across the cyclic aminal ring to afford a bicyclic system with an inverted configuration at the hemiaminal ether carbon atom.(190) Bictegravir (411) retains the antiviral properties of the progenitor drug but demonstrates reduced PXR activation and a longer t1/2 in humans (19 h compared to 14 h), as summarized in Table 8. The additional fluorine substituent on the benzylamine contributed to enhanced solubility, and 411 was approved as part of combination therapy in 2018.(191)
Table 8. In Vitro Profiling Data for 407 and 411
| drug | EC50 (nM) | G140S/Q148R (fold shift) | Fu in human plasma | PXR (% Emax at 15 μM | solubility (mg/mL) | F rat, dog (%) | t1/2 (h, human) |
|---|---|---|---|---|---|---|---|
| 407 | 1.7 | 4.8 | 0.70 | 51 | 53 | 52, 17 | 14 |
| 411 | 1.9 | 2.0 | 0.30 | 18 | 119 | 50, 28 | 19 |
A series of bicyclic hemiaminal ether-based BACE1 inhibitors, of which 413 is a representative, were designed after the furo[3,4-d][1,3]thiazin-2-amine picolinamide LY2886721 (412), a potent BACE1 inhibitor that advanced to phase II clinical trials where it was examined as a potential therapeutic for the treatment of early Alzheimer’s disease.(192) Modeling of 412 bound to the BACE1 active site indicated no specific interaction between the furan oxygen and the protein, suggesting that relocation of this oxygen atom to the adjacent position to create a hemiaminal ether linkage would not compromise an important drug–target interaction. Indeed, the hemiaminal ether 413 exhibited comparable BACE1 inhibitory activity to 412, indicating that the effects of the altered relationship between the ring oxygen atom and the isothiourea moiety that intimately engages the BACE1 enzyme were not detrimental. While the original furo[3,4-d][1,3]thiazin-2-amine core in 412 required a complex, multistep synthesis, the bicyclic aminal intermediate was readily prepared through a one-pot, three-step operation beginning with 414 to produce 418 through the intermediacy of 415, 416, and 417, as depicted in Scheme 20. These bicyclic hemiaminal ethers proved to be very stable under acidic conditions, with no appreciable decomposition observed when incubated at pH values ranging from 1 to 10 at 40 °C for 24 h.(192)
Scheme 20
Scheme 20. Design of 413 and the Synthetic Approach Developed to Access the Core Molecule 418
ORN0829 (421), an orexin antagonist recently identified as a clinical candidate for the treatment of insomnia, is built on a cyclic hemiaminal scaffold that has been shown to possess good chemical stability.(193) The design concept is depicted in Figure 20 and sought to introduce conformational constraint into the amide moiety of 419 by installing the piperidine heterocycle in 420, a modification that fully preserved the binding profile of the progenitor. However, replacing the piperidine ring in 420 with the cyclic aminal in 421 was sufficient to lower lipophilicity to the preferred range for CNS drugs without materially affecting antagonist potency. The two isomers 422 and 423 were 3-fold less potent than 421, while the enantiomer (+)-424 and ring contracted oxazolidine 425 were both much weaker antagonists. All of these analogues demonstrated similar metabolic stability in HLMs, while evaluation of 421 at pH 1.2 and 37 °C for 24 h confirmed chemical stability under acidic conditions. ORN0829 (421) exhibited appropriate pharmacokinetic properties, with an especially rapid tmax and a short t1/2 designed to avoid a hangover of daytime drowsiness the morning following ingestion. The oral bioavailability of 421 was 5.5% in the rat and 61.6% in the dog, with a peak brain concentration in rats of 2.33 nM following a 3 mpk dose, reflecting a brain to plasma ratio of 1:7.(193)
Figure 20
Figure 20. Design principle behind the discovery of 421.
An interesting and unique hemiaminal motif is found in the cephamycins, a group of β-lactam antibiotics and are structurally related to the cephalosporins.(194a) The cephamycins possess an α-disposed methoxy substituent at the C7 position (426, Figure 21), which confers unusually high resistance to degradation by β-lactamases, presumably a reflection of steric hindrance of the adjacent carbonyl moiety of the β-lactam ring.(194b) In these molecules, aminal hydrolysis would be expected to proceed via a carboxonium (carbonylonium) ion intermediate 427 that is disfavored due to the presence of the adjacent carbonyl moiety and the additional ring strain that would be introduced by planarization (Figure 21). Cephamycin C (428) displayed a half-life of 459 h at pH 6.0 and was very stable at pH values ranging from 3.0 to 7.5, with higher degradation rates at pH values beyond this range.(195) However, despite its high resistance toward degradation by several β-lactamases, 428 was active only against Gram-negative bacteria, and modification of the C7 amide element was required to afford cefoxitin (429), which exhibits a broader spectrum of activity that extends to include Gram-positive bacteria.(194) Cefoxitin (429) is administered by injection into a muscle or vein for the treatment of many kinds of bacterial infections, including severe or life-threatening forms.(194b) Other cephamycin derivatives include cefotetan (430), which incorporates an unusual C-7 thioacetal-containing amide moiety, and cefmetazole (431), both of which are semisynthetic, while moxalactam (432) is completely synthetic. All of these antibacterial agents contain a 1-methyl-1H-tetrazol-5-yl)thio)methyl C-3 side chain moiety that is susceptible to metabolism to release N-methylthiotetrazole (433, NMTT), which has been associated with hypoprothrombinemia. For this reason, 431 and 432 have been discontinued in the United States, although 430 remains on the market.
Figure 21
Figure 21. Structure of the carboxonium (carbonylonium) ion intermediate that would be formed if 426 hydrolyzed by loss of the amine substituent.
The development of the orally bioavailable, mechanism-based, polymorphonuclear leukocyte (PMN) elastase (PMNE) inhibitor L-694,458 (438, DMP-777) originated with the relatively simple azetidinone (±)-434.(196a) However, 434 was rapidly hydrolyzed even under mild conditions with a disappearance t1/2 of 2 h at pH = 8.0 and 25 °C while virtually instantaneous decomposition was observed in human blood at 25 °C, reflecting the inherent reactivity of the multiple electrophilic centers. The O-acetyl group, which was considered to be unstable toward nucleophiles and/or esterases, was replaced with a 4-carboxylic acid-substituted phenol, with the resulting 435 possessing improved hydrolytic stability (disappearance t1/2 = 9 h at pH = 8.0 and 25 °C) and improved aqueous solubility while retaining potent mechanism-based, enzyme inhibitory activity. However, since 435 was still susceptible to both N-deacylation and β-lactam ring opening, the N-benzylcarbamoyl analogue 436 was prepared in an attempt to slow the N-deacylation process. This molecule offered higher chemical stability with a t1/2 of >80 h, presumably because the carbamoyl moiety is intrinsically less electron-withdrawing than an acyl group. The stability of the β-lactam nucleus in 436 was further enhanced by introducing a second alkyl group at C3, which projects into the S1 subsite of the enzyme. The additional substituent sterically interferes with nucleophiles approaching the β-lactam carbonyl, with 3,3-diethyl substitution providing the optimal balance of stability, inhibitory potency, and in vivo efficacy.(196b) Incorporation of a (R)-n-propyl substituent at the benzylic methylene resulted in a further 100-fold improvement in inhibitory potency compared to the unsubstituted precursor. Further modifications to both phenyl rings led to the identification of L-680,833 (437) as a potent, orally active PMNE inhibitor.(196c) L-680,833 (437) was completely orally bioavailable in rats although less so in monkeys (F = 23%), and the terminal elimination t1/2 values were 2.3 and 5.8 h in rats and rhesus monkeys, respectively, following a single IV dose. These data also confirmed the improvement in intrinsic chemical and metabolic stability. L-680,833 (437) was selected as a development candidate but was subsequently replaced with L-694,458 (438), which was advanced into phase I clinical trials in adult patients with cystic fibrosis.(196d) L-694,458 (438) had higher oral bioavailability than 437 in rhesus monkeys (39% compared to 23%) but lower in rats (65% compared to 100%). A 40 mpk oral dose administered to rhesus monkeys resulted in a protracted plasma concentration–time profile characterized by a delayed tmax (8–24 h) and a long terminal t1/2 of 6 h. The major metabolite in human and rhesus monkey liver microsomes was the catechol resulting from cleavage of the methylenedioxy moiety. In RLM, the primary metabolic pathway was oxidation of the basic amine to give the N-oxide of the methyl-substituted piperazine nitrogen atom. Therefore, the embedded aminal functionality in these inhibitors appeared to be both chemically and metabolically stable. The chemical stability can be attributed to the reduced availability of the electrons on the nitrogen atom to promote expulsion of the substituted phenol moiety and the strain that would be introduced into the four-membered ring by iminium formation (Scheme 21).
Scheme 21
Scheme 21. Degradation Pathway for 438 Involving the Departure of the Phenol Moiety, A Process That Is Disfavored Electronically and by the Introduction of Strain in the Azetidinone Ring
The widely prescribed sleeping medication eszopiclone (441) features an embedded O-acylated (N,O)-hemiaminal, which is sufficiently stable both chemically and metabolically to be 80% oral bioavailable in humans.(197) Eszopiclone (441) is rapidly absorbed after oral administration, with a tmax ranging from 1 to 1.3 h, thus leading to a quick onset of action. The two major metabolites identified result from N-demethylation of the tertiary amine to give 442 and oxidation of the basic piperazine nitrogen atom to the N-oxide 443 in the liver.
Nucleoside Analogues
The (N,O)-hemiaminal moiety is a structural motif found in the majority of ribose-based nucleoside and nucleotide analogues that are used to treat a range of viral infections and cancers.(198) The (N,O)-hemiaminal linkage in nucleosides is hydrolytically labile under acidic conditions and has presented problems in the development of some ribose-based nucleoside analogues.(199,200) Hydrolytic reactivity is sensitive to the structure of both the ribose and the base, with 2′,3′-dideoxy nucleosides more labile than 2′-deoxyribonucleoside analogues, which, in turn, are more labile than ribonucleosides, as captured by the data compiled in Table 9 for a series of adenine nucleosides 444–450.(199) The higher stability of ribonucleosides has been attributed to the presence of the electronegative 2′-oxygen atom, which destabilizes the oxacarbonium ion intermediate (Scheme 22).(199) Moreover, purine derivatives are considerably more reactive than pyrimidine-based derivatives, and the stability of both is influenced by structural modifications to the heterocycle.(199) The reaction is believed to occur via an acid-catalyzed dissociation of the base after protonation, with glycosyl bond rupture the rate-determining step reflecting an A1-type of mechanism (Scheme 22).(199b,c,e) Despite these concerns, many nucleoside and nucleotide analogues incorporating modified ribose moieties have been successfully developed into important, orally administered drugs.(198)
Scheme 22
Scheme 22. A1 Mechanism of Acid-Catalyzed Hydrolysis of Nucleosides
Table 9. Rate Constants for the Acid-Catalyzed Hydrolysis of a Series of Adenine Nucleosides 444–450(199d)
The 2′,3′-dideoxynucleosides dideoxycytidine (ddc, zalcitabine, 451) and dideoxyinosine (ddI, didanosine, 452) are early examples of nucleoside-based inhibitors of HIV-1 reverse transcriptase developed to treat HIV-1 infection.(198) Due to the absence of hydroxyl substituents at the 2′- and 3′-positions of the ribose ring, both compounds are sensitive to glycoside cleavage under acidic conditions. For example, ddA (447) undergoes acid-catalyzed degradation with a rate constant that is 42,000 times faster than adenosine (444), which can be attributed to the removal of the inductive electron-withdrawing effect of the 2,3-hydroxyl substituents which would destabilize the oxocarbonium intermediate.(199d) Degradation of ddA (447) upon exposure to gastric acid following oral administration gave adenine (453), which is further metabolized to give 2,8-dihydroxyadenine (454), which concentrates in renal tubules where it crystallizes causing nephrotoxicity.(201) ddA (447) also undergoes cellular deamination to ddI (452) which is converted via 456 to ddA-5′-triphosphate (457), the active metabolite responsible for inhibiting HIV-1 reverse transcriptase (Scheme 23).(202) Therefore, ddA (447) can be considered as a prodrug of ddI (452), but the latter offers the advantage of eliminating the release of adenine upon acid-mediated degradation and thus avoiding the potential for nephrotoxicity. However, ddI (452) is still susceptible to acid hydrolysis upon oral administration while its limited solubility at low pH values presents a problem for formulation. An early oral formulation involved large buffered tablets containing calcium carbonate and magnesium hydroxide buffers designed to help neutralize the stomach acid and possibly improve its solubility, but the resulting large and bitter-tasting pills were not only difficult to take but also caused diarrhea and other GI side effects.(203) Ultimately, an enteric coated form using small capsules was developed to protect ddI (452) from hydrolysis in the acidic milieu of the stomach and facilitate absorption from the intestine. The enteric coated form delivered higher oral bioavailability than the buffered tablet (36% compared to 25%), but lower than the oral solution (or reconstituted powder) administered with an antacid (F = 41%).(203) ddI (452) became the second drug marketed to treat HIV-1 infection in the United States when it was approved by the FDA in 1991.(198)
Scheme 23
Scheme 23. Degradation and Metabolism of 447
In contrast to ddA (447), dideoxycytidine (ddC, zalcitabine, 458) showed good stability in acid and was not subject to appreciable metabolic deamination to give dideoxyuridine (459) in either mice or humans although this pathway was measurable in monkeys.(204a) The primary metabolic pathway in the intracellular environment involved sequential phosphorylation to the monophosphate 460, the diphosphate 461 and finally dideoxycitidine-5′-triphosphate (ddC-TP, 462), the active metabolite (Scheme 24). ddC (458) exhibited an oral bioavailability of 80% in humans, which confirmed its stability in the gut, and became the third drug approved to treat HIV-1 infection in the US in 1992.(204b) However, 458 was discontinued in 2006 because of an inconvenient thrice daily dosing frequency as well as its association with serious side effects such as painful peripheral neuropathy.
Scheme 24
Scheme 24. Intracellular Metabolism of 458
An electronegative fluorine was introduced at C-2′ of the ribose of ddA (447) and ddI (452) as a strategy to destabilize the oxocarbonium ion intermediate in the hydrolytic mechanism, thus decreasing the rate of hydrolysis (Scheme 25).(205−207) Indeed, 463, 2′-F-dd-ara-A (464), and 2′-F dd-ara-I (465) were found to be completely resistant to acid hydrolysis at pH 1 and 37 °C while the respective parent compounds had a t1/2 values of less than 1 min.(205a) The acid stability of 2′-F-dd-ara-A (464) was reflected in its increased oral bioavailability relative to ddA in beagle dogs.(205c) The fluoro analogues 464 and 465 appeared to be comparably potent to the parent compounds toward HIV-1 but were also more cytotoxic while 463 was inactive in a cell culture.(205a)
Scheme 25
Scheme 25. Hydrolysis of 2′-F-ara-ddI and 2′-F-ara-ddA Disfavored by the Presence of the 2′-F Atom, Which Destabilizes the Oxocarbenium Ion Intermediate
Fludarabine (466) and cladribine (467) are first-generation purine nucleoside analogues that were advanced through clinical trials and approved for the treatment of leukemias (Scheme 26).(208−210) The 5′-monophosphate moiety in 466 acts as a prodrug to facilitate formulation since embedded nucleoside is very poorly soluble.(209) One drawback with 466 is the phosphorolytic breakdown of the N-glycosidic bond by the bacterial enzyme purine nucleoside phosphorylase expressed in Escherichia coli found in the GI tract which releases 2-fluoroadenine (469). This presents problems because 469 is metabolized in vivo to 2-fluoro-adenosine triphosphate (470), a toxic metabolite with no anticancer activity (Scheme 26).(209) Cladribine (467) is also a substrate for rapid metabolism by bacterial nucleoside phosphorylases to release 2-chloroadenine (471), which is much less toxic than 2-fluoroadenine (469).(210a,b) Cladribine (467) is also sensitive to hydrolytic degradation at the acidic pH of the GI tract.(210,211a−d) Collectively, these data led to the design of clofarabine (468), a derivative of 467 in which a fluorine atom is installed at the C-2′ position in an attempt to reduce both acid- and enzyme-catalyzed ribose cleavage, thus leading to improved oral bioavailability.(211a−d) Clofarabine (468) was comparable to 467 in potency but more cytotoxic than fludarabine 466 to three human cell lines and one murine leukemia (L1210) cell line.(211a−c) Unlike cladribine (467), clofarabine 468 was stable at pH 2 and significantly more resistant to cleavage by E. coli nucleoside phosphorylase, with the degradation rate approximately one-third that of cladribine 467 and fludarabine 466.(210,211a−d) The combination of both effects translated into enhanced oral bioavailability for 468 (57% compared to 40% for cladribine 467) which was approved for the treatment of pediatric leukemia by the FDA in 2004.(211e,f)
Scheme 26
Scheme 26. Metabolism of 466 and 467
Cytarabine (ara-C, 473), a chemotherapy drug whose synthesis was inspired by the two marine natural products spongothymidine (472a) and spongouridine (472b) which were isolated in the early 1950s, is the backbone of intensive acute myeloid leukemia (AML) therapy.(212,213) Due to its poor permeability across intestinal membranes, ribosidic bond cleavage and deamination by cytidine deaminase in both the gut and liver to produce the biologically inactive uracil arabinoside (ara-U, 475), which is excreted by the kidneys, 473 exhibited poor oral bioavailability (ca. 20%) and a short plasma half-life.(212b) This PK profile necessitates continuous infusion of 473 in order to maintain adequate plasma drug levels, with the dose adjusted based on patient liver and kidney function.(214) More recently, BST-236 (aspacytarabine, 474), a prodrug in which the primary amine of 473 is acylated with asparagine, has been developed to deliver high cellular drug levels while reducing plasma exposure as an approach to mitigating systemic toxicity.(215) Prodrug 474, which is inactive and nontoxic and resists deamination in the systemic circulation by virtue of derivatization of the metabolically vulnerable amine, enters leukemic cells intact where it gradually releases 473 via nonenzymatic hydrolysis, resulting in cell death. Aspacytarabine (474) is currently in phase 2b clinical trials for the treatment of aged adult patients (75 years or older) with AML.
An early effort to investigate the impact of fluorine substitution on the ribose ring led to the synthesis of 2′-F-arabinonucleoside (F-ara-C, 476), which demonstrated comparable inhibitory activity toward L1210 leukemia cells as 473 (Figure 22)(216) However, the deamination rate for 476 was similar to 473 resulting in less than robust antitumor activity in mice.(198,217) Structural evolution by further modification at the C-2′ position with geminal difluoro substitution afforded gemcitabine (dFdC, 477), an effective antitumor agent marketed as Gemzar.(218) The two fluorine atoms in 477 influence the conformation of the ribose ring in a unique fashion in which the 2′-carbon atom is deformed out of the plane of the furan ring, a shape distinct from the more conventional north or south nucleoside conformation that may contribute to its enhanced biological activity.(198b) Gemcitabine (477) is administered via intravenous infusion due to its poor intestinal permeability and significant deamination to its inactive uridine metabolite 2,2-difluorodeoxyuridine (dFdU, 478) by deoxycytidine deaminase in both human plasma and liver, both of which contribute to the low, 10%, oral bioavailability (Figure 22). These problems have been circumvented by the development of an orally active prodrug, LY2334737 (479) in which the exocyclic amine is acylated with the lipophilic valproic acid, blocking the site of deamination while enhancing membrane permeability.(219) Prodrug 479 showed good chemical stability (approximately 21% decomposition at pH 1 but completely stable after 4 h at 40 °C, pH 6–8) and was resistant toward enzymatic degradation, with no appreciable hydrolysis observed in small intestine homogenates.(219) In addition, the in vitro hydrolysis rate in human liver incubations was relatively low. These data suggested that the prodrug would transit the GI tract as the intact prodrug due to its chemical and enzymatic stability while low levels of activation in the liver by carboxylesterase-2 would provide for a sustained delivery of 477 to the systemic circulation.(219b) Indeed, 479 demonstrated oral efficacy in human colon cancer xenografts in mice and the molecule was advanced into phase I clinical trials.
Figure 22
Figure 22. Evolutionary path from 472–477.
Sofosbuvir (480) is a notable and prominent example among 2′-fluorinated antiviral nucleoside and nucleotide analogues (Scheme 27).(220) The phosphate prodrug moiety of 480 is unmasked in the liver to give the monophosphate 481 which is converted to its active triphosphate 482, a potent inhibitor of HCV NS5B polymerase (Ki = 0.42 μM) with a long intracellular t1/2 of 38 h. PSI-6206 (483), the nucleoside derived from 481, was inactive in the HCV replicon assays due to its poor enzymatic phosphorylation.(220) Sofosbuvir (480) displayed significant potency in the HCV subgenomic replicon assay, produced high levels of triphosphate 482 in primary hepatocytes and in the livers of rats, dogs, and monkeys following oral administration. Sofosbuvir (480) demonstrated robust antiviral efficacy in the clinic and is a component of several combination therapies that produce cure rates of >95% in all patient populations. In 2015, 480 was designated as an essential medicine by the WHO.
Scheme 27
Scheme 27. Structure of 480 and Its Intracellular Metabolic Pathway to the Active Triphosphate 482
As observed with 2′,3′-dideoxynucleosides, the chemical stability of 2′,3′-dideoxy-2′,3′-didehydronucleosides also depends on the identity of the base moiety.(221) Both stavudine (d4T, 484) and d4U (485) exhibit good stability under acidic conditions (t1/2 = 26 and 15 h, respectively, at pH 1) despite the potential to form the presumed stabilized 2,5-dihydrofuran-2-ylium intermediate 489 by an A1 mechanism which affords the furan 490 (Scheme 28), while d4C (486) degraded relatively quickly when exposed to low pH conditions (t1/2 = 0.2 h at pH = 1), presumably a function of the facility for protonation of the base.(221) The poor oral bioavailability of d4G (487) has been attributed to its highly labile nature under acidic conditions since this nucleoside degrades with a t1/2 of <2 min at pH = 2.(221b,222) Stavudine (484) is one of the most orally bioavailable nucleoside analogues (F ∼ 100% in humans) and although its elimination t1/2 in humans is relatively short (1.6 ± 0.23 h), the active triphosphate metabolite exhibits an intracellular t1/2 estimated to be 7 h, supporting BID dosing of the drug.(223) Stavudine (484) was approved for use by the FDA in 1994 but it has been gradually phased out since 2010 due to its association with metabolic toxicity and long-term complications such as lipoatrophy, peripheral neuropathy, and lactic acidosis.
Scheme 28
Scheme 28. Proposed Decomposition Pathway for 2′,3′-Dideoxy, 2′3′-Didehydro Nucleoside Analogues
Acyclic nucleoside analogues incorporating hemiaminal motifs can also possess adequate stability for oral delivery as demonstrated by acyclovir (492) and ganciclovir (493) which are guanosine mimics licensed to treat herpes simplex virus (HSV) and human cytomegalovirus (HCMV) infections, respectively.(198,224) Both compounds exhibit low oral bioavailability attributed to poor membrane permeability and modest aqueous solubility rather than hydrolytic instability of the acyclic, formaldehyde-based aminal functionality. However, derivation of the primary hydroxyl moiety as the l-valine ester increased the oral bioavailability in humans from 15% to 54% for acyclovir in the context of 494 and from 9% to 65% for val-ganciclovir (495).(225) While introduction of the prodrug moieties resulted in enhanced solubility, the major factor subtending the improved oral bioavailability is their recognition by the PEPT1 transporter which facilitates absorption from the lumen of the small intestine, with the active drugs released by esterases in mucosal tissue.(226)
(O,S)-Acetals (R–O–C–S–R′)
(O,S)-Acetals are considerably more stable than (O,O)-acetals because sulfur has a much reduced tendency toward protonation than oxygen due to its lower electronegativity (2.58 for S compared to 3.44 for O) which translates into low basicity.(227) Consequently, expulsion of the sulfur to generate a carboxonium (carbonylonium) intermediate is not favored (Scheme 29). If the oxygen atom protonates, the resulting carbenium/sulfonium species is expected to be poorly stabilized since, as a third period element, the lone pairs of electrons on sulfur reside in 3p orbitals which do not overlap well with the 2p orbitals on carbon (Scheme 29).(228) This effect may be exacerbated by the longer C–S bond compared to a C–O bond and the overall circumstance is that the carbenium/sulfonium intermediate (Scheme 29) is not readily stabilized by sulfur. Consistent with the hydrolysis rate being dependent on the stability of the carbenium intermediate, 2-(4-methoxyphenyl)-1,3-dioxolane hydrolyzes 1330-fold faster in water at 30 °C than the corresponding 1,3-oxathiolane.(227b) However, similar to (O,O)-acetals, the stability (O,S)-acetals also shows dependence on the nature of the C2 substituent, as shown by the rate constants for hydrolysis of compounds 496a–e in aqueous dioxane in the presence of 1 M HCl at 30 °C compiled in Scheme 29. The electron donating OMe reduces hydrolytic stability by 40-fold while an electron-withdrawing NO2 increases hydrolytic stability by 40-fold.(227b)
Scheme 29
Scheme 29. Acid-Catalyzed Decomposition Pathway for (O,S)-Acetals and Kinetic Data for Hydrolytic Degradation
The 3′-thionucleoside 497 (3TC, lamivudine) was discovered in 1998 and evaluated initially as the racemate BCH-189, a mixtue that demonstrated potent antiviral activity in cell culture.(229) The design rationale to replace the 3′ carbon atom of the ribose ring in ddC (458) with a sulfur atom was based on the anticipation that the shape mimicry of the ribose ring as well as the electronic environment in the 3′ region would play an important role in the activity and selectivity of the nucleoside analogues.(229) Both the unnatural l-isomer 497 and the natural d-enantiomer 498 exhibited similar potency, which, at the time, was very surprising since all previously known active nucleoside analogues possessed the natural d-sugar configuration. Interestingly, 498 inhibited host cell DNA polymerase, a source of toxicity with nucleoside analogues, while unnatural l-enantiomer 497 was devoid of this activity. Lamivudine (497) possessed favorable pharmacokinetic properties (F = 86%; t1/2 = 13–19 h in humans), which confirmed the stability of the (O,S)-acetal functionality in the acidic milieu of the stomach, and was approved by the FDA in 1995 and it is included in the WHO’s List of Essential Medicines.
Soon after the disclosure of 497 in 1989, a series of 5-substituted analogues was explored from which the 5-fluoro analogue emtricitabine (FTC, 499) offered a similar antiviral and toxicity profile to the prototype.(230) In this series, the unnatural l-(−)-enantiomer (499) was approximately 100-fold more potent than the natural d-(+) isomer 500. Also, in contrast to 497 and 498, neither 499 nor 500 showed any cellular toxicity. The antiviral potency and tolerability of 499 are comparable to 497, and the drug was approved for use in the US in 2003. Currently, over 90% of the HIV-1-infected patients in the US are prescribed with either 497 or 499 and, from this perspective, the replacement of the 3′-carbon of the ribose ring with a sulfur atom to form an (O,S)-acetal has had a profound and long-lasting impact on HIV-1 therapy.
The value of the sulfur atom in the context of 497 and 499 is further underscored by the dioxolane homologue troxacitabine (L-OddC, 501) and its 5-fluoro analogue 502, both of which exhibit potent antiviral activity toward HIV-1 and HBV but also demonstrated significant cellular toxicity due to inhibition of host DNA polymerases.(231) The oral absorption of 501 in rats was slow, resulting in highly varied bioavailability between individual rats that amount to 41 ± 27% based on urinary excretion data and 37 ± 25% based on plasma exposure data; therefore, 501 was administered via an IV infusion in clinical studies.(232c,d) The (O,S)-acetal 497 offers improved pharmacokinetic properties compared to the acetal 501 with an oral bioavailability of 86% in humans. Due to its selective toxicity toward several solid tumor cell lines, including hepatocellular and prostate cell lines as well as its activity against solid tumor growth in several human xenograft models, 501 was advanced into phase III clinical trials for cancer treatment using an IV infusion. However, further development of 501 was discontinued for business reasons.(231a,232,233)
l-(+)-1-[4-(Hydroxymethyl)-1,3-dioxolan-2-yl]-5-fluorouracil (504) represents a rare example of a triheteroatomic motif in which three heteroatoms are bound to a single sp3 carbon atom.(234) While the compound was fully characterized, it decomposed upon purification by silica gel chromatography (Scheme 30). The stability of the carboxonium (carbonylonium) ion 506 presumably contributed to the facile cleavage of the glycosyl bond to release the base 505. A subsequent, regioselective SN2 substitution gives the formate 507, which hydrolyzes to the diol 508 (Scheme 30). The chemical instability associated with 504 suggests that simple unstabilized triheteroatomic motifs may be poor vehicles for oral drug design.
Scheme 30
Scheme 30. Decomposition of 504 and Reassembly to Give 507 and Diol 508
An (O,S)-acetal moiety is a feature of the dual SGLT inhibitor sotagliflozin (292), developed for its potential to treat both type I and II diabetes mellitus.(235a) This compound displays good oral bioavailability and a long half-life in humans. Interestingly, the corresponding methoxyglycoside 509 is a selective SGLT2 inhibitor; so, in this context, simply switching from a methoxy to a thiomethyl substituent transforms a selective SGLT2 inhibitor into a dual inhibitor. LX2761 (510) is another thiomethyl-containing dual SGLT inhibitor that exhibits balanced potency but acts locally in the GI tract where SGLT1 is expressed and may offer an advantage over typical SGLT2 inhibitors, which are less effective in lowering blood glucose in patients with impaired renal function.(235b,236)
The thioglycoside MK-8719 (512) is a potent O-GlcNAcase (OGA) inhibitor that was advanced into clinical trials for the treatment of neurodegenerative disorders.(237) The hydroxymethyl-substituted, carbohydrate-based lead thiamet-G (511) showed poor membrane permeability and marginal brain exposure, consistent with its high TPSA value (105 Å2). Transformation of the hydroxymethyl substituent to a difluoromethyl moiety reduced the TPSA to the desirable range for CNS drugs (80 Å2), leading to the discovery of 512, which demonstrated good brain penetration, high metabolic stability, and other favorable pharmacokinetic properties. MK-8719 (512) was advanced into phase 1 clinical trials, although further development appears to have been abandoned.
Sodium taurocholate cotransporting polypeptide (NTCP), a membrane transporter that plays an important role in bile acid uptake, has been recognized as a cellular receptor for both hepatitis B virus (HBV) and hepatitis D virus (HDV).(238) Using a cell-based screening assay, cyclosporine A (CsA, 513), a cyclic peptide widely used in the clinic as an immunosuppressive agent for organ transplantation patients, was identified as a weak NTCP inhibitor, IC50 = 5.78 μM. In an effort to enhance NTCP inhibitory potency while minimizing the inherent immunosuppressive activity, a scaffold-hopping strategy involving a 1,4-ring closure was developed.(239) Cleavage of the olefin of 513 gave an aldehyde and cyclization with the pendent 4-hydroxyl functionality formed a hemiacetal, a versatile synthetic precursor to both acetals and hemithioacetals. The two hemithioacetals 514a and 514b, of undetermined absolute configuration, showed potent inhibition of HBV/HDV infection by specifically blocking NTCP, whereas their acetal counterparts were much less active. Unfortunately, the more active isomer 514b was the minor product from the reaction mixture, and purification proved to be challenging. Despite its size and molecular weight (MW = 1389), 514a exhibited oral bioavailability of 18% and a t1/2 of 5.8 h in mice, with a dose of 30 mg/kg administered by oral gavage providing protection of HDV-susceptible mice from an HDV infection. Importantly, the transformation of 513 to the (O,S)-acetal in 514a eliminated its immunosuppressive activity
.
.Thioacetals and Thioketals (R–S–C–S–R′)
Thioketals and thioacetals are considerably less susceptible to acid-mediated hydrolysis than ketals because sulfur is less prone to protonation than oxygen, and the intermediate carbenium/sulfonium ion is not adequately stabilized, as discussed above (Scheme 31).(240) Moreover, sulfur is a better nucleophile than oxygen, so it would be expected to more readily add back to the carbenium intermediate, particularly in the case of cyclic thioketals. In organic synthesis, acidic protocols for the removal of thioketals are typically nonproductive, and this motif is more commonly deprotected by treatment with Hg(II) salts or under oxidative conditions.(241) Hydrolytic stability studies conducted with benzophenone-based thioacetals in aqueous dioxane in the presence of perchloric acid have revealed that the diethyl thioketal is 104-fold more stable than the diethyl ketal but 104-fold less stable than the 1,3-dithiane derived from benzophenone.(240b)
Scheme 31
Scheme 31. Mechanism of the Acid-Catalyzed Hydrolysis of Thioketals
The identification of the first orally bioavailable angiotensin-converting enzyme (ACE) inhibitor captopril (516) in 1975 represented the first successful demonstration of rational, ligand-based drug design.(242) However, 516 is commonly associated with rash and taste disturbances that are attributed to the presence of the free thiol moiety, side effects addressed by enalaprilat (517), which was marketed as its ethyl ester prodrug enalapril (518).(243) Since the discovery of 516, more than 12 ACE inhibitors have been marketed, with spirapril (520), the ethyl ester prodrug of spiraprilat (519), the eighth ACE inhibitor to be launched in 1995.(244,245) The only structural difference between 518 and 520 is the presence of the spirocyclic thioketal ring in the latter and while both compounds have comparable potency and oral bioavailability, 520 exhibits a longer half-life. This is perhaps surprising based on the presence of the two sulfur atoms, which are potentially metabolically labile; however, they are actually quite stable toward metabolism with 519 the primary metabolite of 520.(246) Spiraprilat (519) was specifically designed to be eliminated through dual renal and hepatic clearance pathways, in contrast to most ACE inhibitors, which are subject to predominantly renal clearance; thus, sprirapril can be prescribed to patients with renal impairment.(246,247)
Probucol (521) is a prominent thioketal derivative that was advanced into clinical trials where it was evaluated for its antiatherogenic effects based on an interesting and complex underlying biochemical pharmacology.(248,249) Probucol (521) displays anti-inflammatory and antioxidant activities that contribute to its antiatherogenic properties and the compound also modestly reduces low-density lipoprotein (LDL)-associated cholesterol levels in vivo, although the two properties appear to be unrelated.(249) However, the clinical utility of 521 has been limited by a concomitant reduction in high-density lipoprotein (HDL)-associated cholesterol levels and QTc interval prolongation observed in some patients, and while used extensively in Japan, 521 was withdrawn in many markets with the arrival of statin-based cholesterol-lowering drugs.(248) Probucol (521) exhibits poor bioavailability and appears to be extensively metabolized including the spirocyclic bis-quinone 522, although available data on the metabolic fate appears to be sparse.(250)
Analogues of 521 have been extensively explored as orally bioavailable compounds. Succinobucol (523) is an anti-inflammatory and antioxidant agent that inhibits inducible VCAM-1 and MCP-1 expression and human aortic cell proliferation that was advanced into clinical trials to assess its potential in the treatment of atherosclerotic disease.(251) Succinobucol (523) is stable in aqueous CH3CN for extended periods (weeks) at room temperature and in mild acid or base where ester cleavage was of concern. However, the adjacent tert-butyl substituents are presumed to confer sufficient steric hindrance to protect the ester moiety such that 523 is not a prodrug of 521 in preclinical species and humans.(251) Succinobucol (523) was the major drug component in plasma following oral dosing of [14C]-labeled material to dogs and rats while 94–98% of drug-related material in the plasma of humans after oral administration was an unchanged parent. Subsequently, the alkylated acids 524 and 525 were advanced into clinical trials as anti-inflammatory agents designed to avoid the formation of the bis-quinone metabolite 522.(250)
ABC-99 (526) is the thioacetal analogue of doxofylline (64) that, like its progenitor, is an inhibitor of bronchospasm in vivo following oral administration believed to be a function of lung cAMP PDE inhibition and adenosine A2 agonism.(252) However, 526 is also mucolytic and exhibits antiinflammatory properties following oral dosing. When incubated with RLM for 30 min, 526 was the major material present, but the trans-sulfoxide 527 and the cis-sulfoxide 528 were identified as metabolites by careful comparison with authentic samples (Scheme 32).(252e) These metabolites appear to be the result of the action of flavin-containing monooxygenases (FMOs), and there was no evidence for the formation of bis-sulfoxides, sulfones, or, as observed with 64, hydroxylation at the thioacetal methine carbon, leading to ring opening.(252e)
Scheme 32
Scheme 32. Metabolism of 526 in RLM
(N,S)-Acetals and Ketals (R–N–C–S–R′)
(N,S)-Acetals are much more resistant to acid degradation than the corresponding (N,O)-acetals because the carbenium intermediate after the departure of the cationic amino group is less stable due to lack of stabilization from the adjacent sulfur atom relative to oxygen, as previously discussed. It has been estimated that a thiazolidine ring 529 (Scheme 33A) is more stable than an analogous oxazolidine ring 533 (Scheme 33B) by 4 orders of magnitude.(253) Thus, it took several hours to cleave thiazolidine 529 in aqueous TFA in contrast to just a few minutes for the oxazolidine homologue 533.(181a) The stability of (N,S)-acetals also depends on the nature of the C2 substituents: the dimethylthiazolidine 536 underwent ring opening in the presence of TFA within a few hours to give 537, while the unsubstituted analogue 538 was resistant to dissolution in strong acid (Scheme 34).(181a)
Scheme 33
Scheme 33. Mechanism of the Acid-Catalyzed Hydrolysis of (N,S)- (A) and (N,O)-Ketals (B)
Scheme 34
Scheme 34. Hydrolysis of 536–537 and Structure of the Stable Analogue 538
An acylated (N,S)-acetal is a ubiquitous structural element in the penicillin and cephalosporin β-lactam antibiotics 539 and 541, respectively, exemplified by amoxicillin (540) and cephalexin (542).(254) β-Lactam antibiotics interrupt bacterial cell wall synthesis by inhibiting transpeptidases, the enzymes responsible for cross-linking peptides to form the peptidoglycan-based cell wall architecture.(255) Amoxicillin (540) and cephalexin (542) are two of the top ten prescribed antibiotics in the world. Both compounds show excellent oral bioavailability in humans, suggesting that the (N,S)-acetal has good chemical and metabolic stability despite the strain inherent to the fused ring system. Biotransformation studies of 540 in HLMs revealed seven metabolites which resulted from oxidation of one of the methyl substituents (543), which was further oxidized to 544 and 545, hydroxylation of the phenol (546), which underwent oxidative deamination of the primary amine to afford ketoamide 547, decarboxylation of the acid to give 548 and conjugation with glucuronic acid to afford 549 or 550 (the specific structures were not determined), as summarized in Scheme 35.(256) Thus, the (N,S)-acetal remained intact, and there was no indication of oxidation at sulfur, presumably due to the steric hindrance afforded by the adjacent geminal dimethyl substitution. Amoxicillin (540) incorporates a phenol, a potentially problematic group in drug design, should it be metabolized to a reactive quinone intermediate. However, in this case, no glutathione conjugates were detected in the HLM assay, suggesting that phenol oxidation to a quinone was not an issue. However, 540 and 542 display relatively short elimination half-lives in part due to their low protein binding.(257)
Scheme 35
Scheme 35. Metabolism of 540
The discovery of clavulanic acid (393) as an irreversible β-lactamase inhibitor in 1976 prompted an intensive search for other mechanistically related compounds, an effort that culminated in the identification of the penicillin-based sulfones exemplified by sulbactam (551), tazobactam (552), and (more recently) enmetazobactam (553).(258−261) The presence of the sulfone functionality appears to abolish inherent antibacterial activity in this chemotype but is important for β-lactamase inhibition by functioning as a leaving group similar to the oxygen atom in the (N,O)-hemiaminal element of 393. The mechanism of action of the penicillin-based sulfones involves ring opening of the thiazolidine 1,1-dioxide ring of 555 that is triggered by β-lactam ring opening to form the imine intermediate 556, which engages in a similar sequence of reactions to 393 to inactivate β-lactamase (Scheme 36).(258,261) The sole difference between 552 and 553 is the methylation of the triazole heterocycle in the latter, which results in the formation of a zwitterionic species that contributes to enhanced bacterial cell penetration. Enmetazobactam (553) is undergoing phase III clinical evaluation as part of combination therapy with β-lactam antibiotics for the treatment of serious Gram-negative infections.
Scheme 36
Scheme 36. Mechanism of β-Lactamase Inhibition by 554
The O-acylated intermediate 556 can hydrolyze to regenerate the active β-lactamase, a potential Achilles heel that was addressed by the pyridylmethylidene sulbactam 557, which was designed to subvert this pathway (Scheme 37A).(258a) Thus, nucleophilic addition of the pyridine nitrogen to the initially formed conjugated imine 558 to give 559, and subsequent aromatization furnished a highly stable indolizine adduct 560 that contributed to the observed enhanced inhibitory activity.(262) In order to rationalize the enzyme inhibition process, NaOMe was used as a surrogate for the serine of the enzyme (Scheme 37B). Thus, treatment of 561 with one equivalent of NaOMe in CH3OH at room temperature for 10 min gave indolizine 563, which was isolated in 85% yield after methylation to give 564. When tested with one E. coli β-lactamase, 557 demonstrated 100% inhibition at 1 μM compared to 81% inhibition for 393. In contrast, the phenyl analogue 565, which cannot react to form an indolizine adduct, was much less active (28% inhibition at 1 μM). Further modification of the geminal dimethyl groups led to LN-1–255 (566), which demonstrated significantly improved activity against several carbapenem-hydrolyzing class D β-lactamase enzymes (CHDLs) compared to 552.(263a) In a murine pneumonia model caused by carbapenem-resistant A. baumannii strains expressing carbapenem-hydrolyzing, class D β-lactamases, a combination of 566 with imipenem provided higher protection against pneumonia than the treatment with imipenem alone, suggesting that 566 may have potential to treat infections caused by A. baumannii isolates carrying CHDLs.(263b)
Scheme 37
Scheme 37. (A) Mechanism of β-Lactamase Inhibition by 557; (B) Reaction of 561 with Methoxide
Benzbromarone (567) is a highly effective uricosuric agent that was withdrawn from the market in several countries after reports of serious hepatotoxicity, likely due to the inhibition of mitochondrial function by metabolites.(264) In an attempt to mitigate mitochondrial inhibition, a series of aryl benzamides was explored, from which indoline 568 exhibited reduced mitochondrial inhibition while maintaining urate uptake inhibitory activity.(265a) However, the oral exposure of 568 in rats was significantly reduced (Cmax = 1.36 μg/mL compared to 4.42 μg/mL for 567) due to metabolic instability. Replacement of the core heterocycle with a benzothiazolidine dioxide in 569 resulted in enhanced exposure with a Cmax = 3.81 μg/mL. Benzothiazolidine dioxide 569 also exhibited a favorable CYP2C9 inhibition profile (IC50 = 57 μM compared to 41 nM for 567) but its urate uptake inhibitory activity was compromised. Optimization of the phenyl ring substitution pattern led to the identification of dotinurad (FYU-981, 570) as a potent, selective urate reabsorption inhibitor (urate transporter 1 inhibitor) for the treatment of hyperuricemia.(265a) Following oral administration of radiolabeled 570 to rats, cynomolgus monkeys, and humans, the major component in plasma was the parent drug (81.9, 92.0, and 80.9%, respectively), with the major metabolites like phenol sulfate, the 6-hydoxyl derivative, and 3,5-dichloro-4-hydroxy-benzoic acid, which are metabolites that were also observed in vitro along with the glucuronide of the phenol.(265b) The phenol glucuronide and phenol sulfate were the major metabolites detected in the urine of cynomolgus monkeys, while only small amounts (0.1–0.7%) of the metabolite reflecting loss of formaldehyde from the heterocyclic ring were observed in the in vitro and in vivo studies. Dotinurad (570) was approved in Japan in February 2020 as a new uricosuric medication for the treatment of hyperuricemia with or without gout.
TUG-1375 (573) is a potent and effective thiazolidine-based free fatty acid receptor 2 agonist (pKi = 6.7; cAMP pEC50 = 7.1, Emax = 86% relative to propionic acid) that has been explored as a tool molecule to assess its potential in the treatment of inflammatory and metabolic diseases.(266) The lead compound 571 that subtended the discovery of 573 was based on a 5-substituted proline core, a scaffolding element that interfered with efficient SAR studies due to the need for a complex, multistep synthesis. Using a bioisosteric replacement strategy based on the synthetically more tractable thiazolidine heterocycle exemplified by 572, a series of analogues was rapidly prepared and evaluated, an effort that led to the identification of 573 as a compound with favorable pharmaceutical and PK properties. Incubation of 573 in primary mouse hepatocytes revealed low intrinsic clearance (<8 μL/min/106 cells) with 81% of the parent compound remaining after 1 h and 72% preserved after 2 h, metabolic stability that subtended a t1/2 of 138 min following IV administration and 32% oral bioavailability. The (N,S)-acetal core also provided improved potency compared to the proline-based prototype while not posing a significant chemical stability issue.(266)
The proline-derived homophenylalanine derivative 574 was identified as a potent and highly selective DPP4 inhibitor (IC50 = 0.48 nM) but lacked oral bioavailability.(267a) By replacing the pyrrolidine ring with a thiazolidine, a new series of potent and selective DPP4 inhibitors was developed with 575, the most active analogue.(267b) This compound exhibited good metabolic stability in human and rat liver microsomes and was chemically stable at pH values ranging from 1 to 9 (>90% remaining after 24 h). The limited oral absorption of 575 was overcome by adopting the ethyl ester prodrug 576, which rapidly released 575 in the plasma, and oral administration of 576 to both rats and dogs elicited significant DPP4 inhibition.(267b)
Other prominent thiazolidine derivatives include the inhaled PDE4 inhibitor 577 for the treatment of respiratory disease and the gut-restricted agonist of G protein-coupled bile acid receptor 1 (GPBAR1, TGR5) 578 explored for potential in type II diabetes mellitus and inflammatory bowel disease.(268,269)
(N,N)-Aminals (R–N–C–N–R′)
Simple (N,N)-aminals are more susceptible to ring cleavage than homologous acetals and ketals, attributed to the ready protonation of the amine (580) that leads to a stable imine intermediate 581, which can hydrolyze to 532 via 582 (Scheme 38).(270) The stability of (N,N)-aminals can be enhanced by incorporating electron-withdrawing groups at C2 or acylating either or both of the basic amines. However, the effect on stability is context-dependent, as exemplified by the cyclic acylated aminal hetacillin (583), a prodrug of ampicillin (585), which is unstable in aqueous solution with a half-life of 15–30 min at 37 °C and pH = 7.(271) The geminal dimethyl groups at C2 contribute to the instability of 583 by stabilizing the carbonium ion intermediate 584 (Scheme 39).
Scheme 38
Scheme 38. Mechanism of the Acid-Catalyzed Hydrolysis of (N,N)-Aminals
Scheme 39
Scheme 39. Decomposition of 583 into 585
Pneumocandin B0 (586), also known as hydroxy echinocandin, displayed potent fungicidal activity, but its development was shelved because of a narrow spectrum of activity, insufficient solubility for IV formulation, and chemical instability due to the hemiaminal functionality.(272) Under basic conditions (pH > 8), the cyclic aminal of 586 is cleaved to give an aldehyde intermediate 587, which undergoes spontaneous ring closure to the thermodynamically more stable five-membered N-acyl hemiaminal 588 (Scheme 40). In the presence of acid (pH < 5), protonation of the hemiaminal amine followed by dehydration leads to a highly electrophilic N-acyliminium intermediate 589, which can react with a variety of nucleophiles. When no external nucleophile is available, intramolecular attack by the amide nitrogen occurs to form another aminal 590. Both degradation products are significantly less active than the original natural product.(272b)
Scheme 40
Scheme 40. Structure of 586 and Degradation Pathways under Basic and Acidic Conditions
In an attempt to stabilize the hemiaminal of 586, a cationic aminoethyl ether group was incorporated to form the (N,O)-aminal 591.(273) The amino side chain was beneficial to both the antifungal activity and solubility, which was further increased upon reduction of the primary amide to the amine 592. Diamine analogue 592 exhibited enhanced inhibitory activity toward both Candida and Aspergillus spp., was highly water-soluble and considerably more stable than 586.(273) Nevertheless, the plasma exposure of 592 was poor in the chimpanzee, a good predictor of human PK, and its toxicological profile was of concern (acute toxicity = 30 mpk in mice with an inadequate safety margin). Both issues were circumvented by simply switching from the (N,O)-aminal to the (N,N)-aminal found in caspofungin (593) which showed a 2- to 3-fold improvement in the chimpanzee PK profile over the matched oxygen analogue.(274) Moreover, the acute toxicity of 593 in mice was mitigated, with the tolerated dose increased to 50 mpk, which provided adequate separation from the efficacious dose. The favorable PK profile of 593 was consistent across other preclinical species, with sustained plasma levels and an elimination t1/2 of 9–11 h in humans supporting a once-daily IV dosing regimen.(274) With an optimized formulation, 593 has a 2-year shelf life at 2–8 °C and was the first of the echinocandin class of antifungal agents to be approved in the U.S. to treat invasive aspergillosis after the failure of standard therapy, and it has become one of the most prescribed IV antifungal agents worldwide.(272a)
The isoxazolinone 594 is representative of a series of antibacterial agents modeled after linezolid (595) but which simplifies the structure by removing a chiral center.(275) Chemical stability was of concern, but representative compounds demonstrated excellent stability when exposed to TFA in CH2Cl2 and 1 N HCl in THF, while <1% degradation was observed over 18 h when dissolved in citrate buffer at pH = 4. Under basic conditions at pH = 8.5, the molecules were labile, with loss of the acetamidomethyl moiety occurring in a fashion that was time- and temperature-dependent and amounted to 40% degradation over 18 h. This is presumably a base-catalyzed elimination that reflects the inherent acidity of the isoxazolinone heterocycle, which has a pKa estimated to be <6 based on the value measured for the naphthalene derivative 596.(276) However, solid-state stability was high, with no detectable erosion of compound integrity over 3 years at an ambient temperature. Several members of this chemotype demonstrated oral bioavailability in mice and rats and were active in a mouse model of S. aureus infection following oral administration.(275)
Another prominent drug that integrates an (N,N)-aminal moiety is baloxavir (602) which is marketed as its prodrug baloxavir marboxil (603), the first new influenza antiviral agent approved by the FDA in nearly 20 years.(277) Unlike neuraminidase inhibitors, which prevent nascent virus release from host cells, 602 directly prevents virus replication by inhibiting the cap-dependent endonuclease (CEN) activity of the viral polymerase.(277) The carbamoyl pyridone bicyclic core originated with the weak CEN inhibitor screening lead 597 that lacked a hydrophobic domain, a deficiency that was addressed by the introduction of a benzhydryl moiety to afford 598, which exhibited markedly enhanced CEN inhibitory activity and antiviral potency.(277b) The carboxylic acid was subsequently eliminated to increase membrane permeability and the methoxymethyl side chain replaced with an isopropyl group to address a metabolic soft spot. The resulting analogue 599 exhibited good antiviral potency with an EC50 value of 58 nM in a cytopathic effect (CPE)-based antiviral assay, but the rat IV clearance for this molecule was high (25 mL/min/kg), attributed to a high free fraction in rat plasma (fu = 18%) rather than metabolic instability (79% remaining after 30 min in RLM). A common approach to increase protein binding is to add hydrophobic groups; however, this tactic can adversely impact both biological activity and metabolic stability. To reduce the free fraction while maintaining the other favorable properties, a judicious bioisosteric replacement approach was embraced. Substitution of the C-1 methine with a nonbasic nitrogen atom (due to the α effect) to form a cyclic aminal increased cLogP by 1.4 units, which contributed to a significant reduction in the free fraction from 18% to 3.8% while preserving potent antiviral activity. The metabolic stability of the cyclic aminal was confirmed in RLM, with 86% remaining after 30 min compared to 79% for the C-1 analogue, while IV clearance in the rat decreased from 25 to 11 mL/min/kg. Switching the lipophilic group at N-1 from the acyclic benzhydryl to the cyclic dihydrodibenzothiepine 600 improved antiviral activity by 4-fold; however, this was accompanied by a 3-fold increase in rat IV clearance because of lower metabolic stability and a higher free fraction. Installing a trifluoro-2-propyl substituent at N-3 and doubly fluorinating one of the phenyl rings located in the lipophilic region improved the in vitro and in vivo profile.(278) These efforts led to the discovery of 601 with excellent antiviral activity as well favorable rat IV clearance. In a mouse model of influenza virus infection, 601 showed potent oral efficacy in reducing virus titers in the lung. Simultaneous optimization at N-3 and C-2 culminated in the discovery of 602, which was developed as the prodrug of 603 for the treatment of influenza A and influenza B infections.(277) The prodrug exhibits favorable pharmacokinetic characteristics, including a half-life of 79 h in humans, supporting single daily oral dosing.(279)
An acylated five-membered (N,N)-aminal core was designed as part of the optimization of a series of HIV-1 integrase inhibitors in which a ring fusion was introduced to the bicyclic core of the lead compound 604 in an effort to balance potency and PK properties.(280) These efforts led to spiroaminal 605, which demonstrated excellent intrinsic antiviral activity (wild-type (WT) IC50 = 2.5 nM without human serum) but which was subject to an unacceptably large shift in potency in the presence of human serum (WT IP IC50 = 600 nM with 50% normal human serum, a 240-fold shift), attributed to high protein binding. Incorporation of the polar hydroxyl groups in 606 and 607 reduced protein binding and led to an increase in potency in the presence of serum. However, the hydroxyl group was still not sufficient to provide the desired solubility and permeability, so a double prodrug approach was adopted in the context of 608.(280) Of particular note, no decomposition of the acylated aminal functionality was observed with any of these analogues.
Tomivosertib (eFT508, 612) is an orally bioavailable, potent, and selective inhibitor of mitogen-activated protein kinase interacting kinases 1 and 2 (MNK1/2) that is currently in phase II clinical trials in patients with advanced castrate-resistant prostate cancer.(281) One of the early lead compounds that contributed to the discovery of 612 was the lactam 609, which exhibited moderate dual inhibition of MNK1/2 but lacked adequate kinase selectivity. Thus, an effort was made to target one of the atypical residues in the ATP binding site of MNK1/2, the pre-DFG residue Cys225. Attempts to capture Cys225 with an unsaturated amide Michael acceptor had not been successful, indicative of low reactivity leading to a focus on engaging this residue in a stereoelectronic interaction as a means of enhancing both potency and selectivity. To this end, the lactam was replaced with a pyridone-aminal where the newly introduced lactam carbonyl in 610 engaged in a multipolar interaction with the Cys225 thiol. This kind of stereoelectronic interaction, in which electron density is donated into the amide C═O π* orbital and is described as multipolar in nature, is optimal when the electron donor approaches at the Bürgi-Dunitz angle (Figure 23A).(282) An X-ray cocrystal structure of 610 bound to MNK2 confirmed the design based on the distance and angle between the Cys225 sulfur atom and the carbonyl carbon atom (Figure 23B). The cyclic aminal proved to be essential as the ring-opened product 613 lost activity, in part due to a less than optimal geometry for the Bürgi–Dunitz-type of interaction, although the phenyl homologue 614 was more potent. As anticipated by the design principle, 610 showed significant improvement over 609 in the kinase selectivity profile (>400 kinases), and a similar trend was observed in other pyridone–benzene pairs. Because of its favorable selectivity profile, facile synthesis, and excellent chemical stability, the pyridone-aminal series was prioritized for further optimization. 2-Methyl pyrimidine substitution increased cellular potency by 23-fold (611), while further amino substitution at C6 further improved potency leading to tomivosertib (612). Comparison of the X-ray cocrystal structures of 610 and 612 bound to MNK2 suggested that the Bürgi–Dunitz interaction in the latter was stronger, which may contribute to its superior potency (Figure 23B,C).(281)
Figure 23
Figure 23. (A) The Bürgi–Dunitz angle for the approach of a nucleophile to the carbon atom of a carbonyl moiety; (B) details surrounding the interaction of the thiol of Cys225 with 610; (C) details associated with the interaction of the thiol of Cys225 with 612.
Trazpiroben (615, TAK-906) is an orally bioavailable, second-generation dual dopamine D2/D3 receptor antagonist that is currently in phase IIb clinical studies for the treatment of diabetic and idiopathic gastroparesis, a disease in which stomach emptying is compromised.(283) The cyclic, acylated aminal moiety that is spiroannulated to a piperidine heterocycle and the carboxylic acid moiety are unique structural elements that differentiate 615 from the first-generation medications metoclopramide (617) and domperidone (618), and the second-generation clinical compound metopimazine (NG101, 619).(284,285) Due to its zwitterionic nature, 615 showed marginal brain penetration in rat and dog studies and exhibited low affinity for the hERG channel with IC50 of 15.6 μM, suggesting reduced potential for both the CNS and cardiovascular side effects that have been associated with the first-generation dual dopamine D2/D3 receptor antagonists, which are limited to short-term treatment. In healthy volunteers, 615 exhibited rapid oral absorption and elimination (tmax = ∼1.1 h; t1/2 = 4–11 h) after single and multiple doses.(284) The major metabolite in human plasma was the alcohol 616.(286)In vitro biotransformation studies using human, rat, and dog hepatocytes identified a non-CYP pathway as the primary route of metabolism (57%), which involves multiple cytosolic, NADPH-dependent reductases, including aldo-keto reductase, and short-chain dehydrogenase/reductase, which reduce the ketone moiety of 615 to afford 616. The remainder of the metabolism of 615 is mediated by CYP3A4 and CYP2C8 (43%); however, cleavage of the acylated cyclic aminal does not appear to an issue based on the available data.(286)
An identical fused tricyclic acylated aminal core is present in both 620, a lead inhibitor of respiratory syncytial virus (RSV) fusion, and ML375 (621), the first M5-selective and brain penetrant negative allosteric modulator (NAM) of a muscarinic acetylcholine receptor.(287a,288) The M5-NAM activity of 621 was found to depend upon the absolute configuration of the chiral center with the enantiomeric 622 inactive. Optimization of the RSV activity in 617 focused on improving the pharmaceutical properties and PK profile and culminated in the identification of BTA9881 (623), a single enantiomer that was advanced into phase 1 clinical studies.(287b) In this series, the antiviral activity was also dependent on the absolute configuration of the chiral center with the antipode 624 inactive.(287b)
Conclusion
ARTICLE SECTIONS
Geminal diheteroatomic motifs have found gainful application in drug design and discovery where their unique properties have been successfully utilized to restrict conformation, increase potency and selectivity, improve pharmaceutical properties, mitigate ion channel activity, and provide structural novelty. Despite the general perception about the liability of acetals and ketals toward gastric acid during oral absorption, simple acetal- and ketal-containing compounds can possess sufficient acid stability and metabolic stability to deliver adequate oral bioavailability in preclinical species and humans. Where stability issues arise, an understanding of the fundamental of the underlying organic chemistry provides a basis for the implementation of rational approaches to mitigate problems. These approaches include the incorporation of electron-withdrawing substituents at sites that exert a direct effect upon the diheteroatomic motif and the introduction of proximal basic heteroaryl rings or amines. Conformational rigidification can also serve as an effective strategy to stabilize diheteroatomic motifs, an approach that has been adopted by Nature in the construction of penicillin and cephalosporin β-lactam antibiotics. The less stable cyclic (N,N)- and (N,O)-based aminals generally require a nonbasic amine component which can be achieved by either introducing an electron-withdrawing substituent, most commonly an acyl group, or by incorporating the nitrogen atom into a heteroaryl ring system as exemplified by nucleoside and nucleotide analogues. The acid-stable cyclic (O,S) motif can deliver unique conformational attributes compared to an acetal or ketal, which can result in unexpected pharmacological and PK properties, demonstrated most effectively by the nucleoside analogue lamivudine (497). Most conveniently, geminal heteroatomic motifs can often be readily prepared from simple carbonyl-containing precursors, and their tolerability toward acidic conditions can easily be evaluated in vitro and in simulated gastric acid preparations at 37 °C. Against the backdrop of the successful discovery and development of numerous orally bioavailable drugs that incorporate a broad range of geminal diheteratomic motifs, a refined understanding of their physicochemical properties enables the design and deployment of these structural elements in a fashion that can fully exploit their unique properties. It is hoped that by creating a heightened awareness and understanding of geminal diheteratomic motifs, rather than being viewed as unconventional and problematic, their utility and judicious application in drug discovery will be facilitated.
Author Information
ARTICLE SECTIONS
- Yong-Jin Wu - Small Molecule Drug Discovery, Bristol Myers Squibb Research and Early Development, 100 Binney Street, Cambridge, Massachusetts 02142, United States;
https://orcid.org/0000-0002-3452-6292;
- Nicholas A. Meanwell - Department of Discovery and Chemistry and Molecular Technologies, Bristol-Myers Squibb PRI, PO Box 4000, Princeton, New Jersey 08543-4000, United States;https://orcid.org/0000-0002-8857-1515;
Biographies
ARTICLE SECTIONS
Yong-Jin Wu
Yong-Jin Wu obtained his Ph.D. in organic chemistry from the Memorial University of Newfoundland in 1991 under the guidance of Prof. Jean Burnell. Subsequently, he undertook 3 years of postdoctoral training in natural product synthesis with Prof. Derrick Clive at the University of Alberta and Prof. E. J. Corey at Harvard University. He started his career as a medicinal chemist at Pfizer Central Research in Groton, CT, in 1995 and joined Bristol Myers Squibb (BMS) in Wallingford, CT, in 1999. He has been working at BMS ever since and is currently at the Cambridge, MA facility, where his investigations focus on the discovery of novel kinase inhibitors for immunology, rheumatology, and oncology indications.
Nicholas A. Meanwell
Nicholas A. Meanwell received his Ph.D. from the University of Sheffield and conducted postdoctoral studies at Wayne State University before joining BMS in 1982. He has been associated with the discovery of BMY-433771, an inhibitor of respiratory syncytial virus fusion, the HIV-1 attachment inhibitor temsavir/fostemsavir, the HIV-1 maturation inhibitor GSK-3532795/BMS-955176, and the marketed HCV inhibitors asunaprevir (NS3), daclatasvir (NS5A), and beclabuvir (NS5B). He is the corecipient of a 2014 PhRMA Research and Hope Award for Biopharmaceutical Industry Research and a 2017 ACS Heroes of Chemistry Award. He was the recipient of the 2015 Philip S. Portoghese Medicinal Chemistry Lectureship Award and was inducted into the ACS Division of Medicinal Chemistry Hall of Fame in 2015.
Acknowledgments
ARTICLE SECTIONS
We would like to thank our colleagues Brian Venables and Matthew Patton of Bristol Myers Squibb Research and Early Development, Cambridge, MA, for reviewing the manuscript.
| Abbreviations Used | |
| 5HT | 5-hydroxytryptamine |
| 5-LO | 5-lipoxygenase |
| ACAT | acyl-CoA:cholesterol O-acyltransferase |
| ACE | angiotensin-converting enzyme |
| ADC | antibody–drug conjugate |
| AEA | anandamide |
| AIDS | acquired immunodeficiency syndrome |
| ALL | acute lymphocytic leukemia |
| AML | acute myeloid leukemia |
| ATP | adenosine triphosphate |
| BRD | bovine respiratory disease |
| BTAa | Bicycles from Tartaric acid and Amino acids |
| CB | cannabinoid |
| CEN | cap-dependent endonuclease |
| CFTR | cystic fibrosis transmembrane regulator |
| CNS | central nervous system |
| COPD | chronic obstructive pulmonary disease |
| CPE | cytopathic effect |
| cpKa | calculated pKa |
| CSD | Cambridge Structural Database |
| CSF | cerebrospinal fluid |
| Cyp | cyclophilin |
| CYP450 | cytochrome P450 |
| DAT | dopamine transporter |
| DDI | drug–drug interaction |
| DMAc | dimethylacetamide |
| DHA | dihydroartemisinin |
| DMSO | dimethyl sulfoxide |
| DNA | DNA |
| FAAH | fatty acid amide hydrolase |
| FDA | United States Food and Drug Administration |
| FMO | flavin-dependent monooxygenase |
| FRET | fluorescence resonance energy transfer |
| Fsp3 | fraction of sp3 carbon atoms |
| GABA | γ-aminobutyric acid |
| GAE | general anomeric effect |
| GI | gastrointestinal |
| GlyT1 | glycine transporter |
| GT | genotype |
| HBD | H-bond donor |
| HCV | hepatitis C virus |
| hERG | human ether-à-go-go-related gene |
| HIV-1 | human immunodeficiency virus-1 |
| HLM | human liver microsomes |
| HPMN | human peripheral blood polymorphonuclear monocyte |
| HPV | human papilloma virus |
| HWB | human whole blood |
| MAP kinase | mitogen-activated protein kinase |
| MRSA | methicillin-resistant S. aureus |
| MSSA | methicillin-susceptible S. aureus |
| NBTI | novel bacterial topoisomerase inhibitors |
| NHV | normal healthy volunteer |
| NK1 | neurokinin-1 |
| NMP | N-methyl pyrrolidone |
| OEA | oleoylethanolamide |
| OGA | O-GlcNAcase |
| OX | orexin |
| PDE | phosphodiesterase |
| PEA | palmitoylethanolamide |
| PEG | polyethylene glycol |
| PK | pharmacokinetic |
| PPAR | peroxisome proliferator-activated receptor |
| PXR | pregnane X receptor |
| RLM | rat liver microsomes |
| RNAP | DNA-dependent RNA polymerase |
| RSV | respiratory syncytial virus |
| S1P1 | sphingosine-1-phosphate receptor 1 |
| SCW | streptococcal cell wall |
| SERT | serotonin transporter |
| SGLT | sodium–glucose-linked transporter |
| SP | substance P |
| SPIDER | substance P-induced dermal inflammation |
| SSTR | somatostatin receptor |
| TAMRA | tetramethylrhodamine |
| TFA | trifluoroacetic acid |
| THF | tetrahydrofuran |
| TPSA | topological polar surface area |
| TxA2 | thromboxane A2 |
| U.S. | United States of America |
| WHO | World Health Organization |
| WT | wild-type. |
References
ARTICLE SECTIONS
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- 7(a) Beard, W. A.; Horton, J. K.; Prasad, R.; Wilson, S. H. Eukaryotic base excision repair: new approaches shine light on mechanism. Annu. Rev. Biochem. 2019, 88, 137– 162, DOI: 10.1146/annurev-biochem-013118-111315[Crossref], [PubMed], [CAS], Google Scholar.7ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXht1Wqt7rF&md5=08104c2a8791d94b37f3bf5e091bec9dEukaryotic Base Excision Repair: New Approaches Shine Light on MechanismBeard, William A.; Horton, Julie K.; Prasad, Rajendra; Wilson, Samuel H.Annual Review of Biochemistry (2019), 88 (), 137-162CODEN: ARBOAW; ISSN:0066-4154. (Annual Reviews)A review. Genomic DNA is susceptible to endogenous and environmental stresses that modify DNA structure and its coding potential. Correspondingly, cells have evolved intricate DNA repair systems to deter changes to their genetic material. Base excision DNA repair involves a no. of enzymes and protein cofactors that hasten repair of damaged DNA bases. Recent advances have identified macromol. complexes that assemble at the DNA lesion and mediate repair. The repair of base lesions generally requires five enzymic activities: glycosylase, endonuclease, lyase, polymerase, and ligase. The protein cofactors and mechanisms for coordinating the sequential enzymic steps of repair are being revealed through a range of exptl. approaches. We discuss the enzymes and protein cofactors involved in eukaryotic base excision repair, emphasizing the challenge of integrating findings from multiple methodologies. The results provide an opportunity to assimilate biochem. findings with cell-based assays to uncover new insights into this deceptively complex repair pathway.(b) Drohat, A. C.; Maiti, A. Mechanisms for enzymatic cleavage of the N-glycosidic bond in DNA. Org. Biomol. Chem. 2014, 12, 8367– 8378, DOI: 10.1039/C4OB01063A[Crossref], [PubMed], [CAS], Google Scholar7bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtlOlsbbO&md5=f95f28fcda9f87eba5d9911c368196edMechanisms for enzymatic cleavage of the N-glycosidic bond in DNADrohat, Alexander C.; Maiti, AtanuOrganic & Biomolecular Chemistry (2014), 12 (42), 8367-8378CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)A review. DNA glycosylases remove damaged or enzymically modified nucleobases from DNA, thereby initiating the base excision repair (BER) pathway, which is found in all forms of life. These ubiquitous enzymes promote genomic integrity by initiating repair of mutagenic and/or cytotoxic lesions that arise continuously due to alkylation, deamination, or oxidn. of the normal bases in DNA. DNA glycosylases also perform essential roles in epigenetic regulation of gene expression, by targeting enzymically-modified forms of the canonical DNA bases. Monofunctional DNA glycosylases hydrolyze the N-glycosidic bond to liberate the target base, while bifunctional glycosylases mediate glycosyl transfer using an amine group of the enzyme, generating a Schiff base intermediate that facilitates their 2nd activity, cleavage of the DNA backbone. Here, the authors review recent advances in understanding the chem. mechanism of monofunctional DNA glycosylases, with an emphasis on how the reactions are influenced by the properties of the nucleobase leaving-group, the moiety that varies across the vast range of substrates targeted by these enzymes.
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- 9(a) Yu, S.; Oh, J.; Li, F.; Kwon, Y.; Cho, H.; Shin, J.; Lee, S. K.; Kim, S. New scaffold for angiogenesis inhibitors discovered by targeted chemical transformations of wondonin natural products. ACS Med. Chem. Lett. 2017, 8, 1066– 1071, DOI: 10.1021/acsmedchemlett.7b00281[ACS Full Text.], [CAS], Google Scholar9ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsVOrsb%252FF&md5=7ae303dfa823b91a4cb37b07a8968b65New Scaffold for Angiogenesis Inhibitors Discovered by Targeted Chemical Transformations of Wondonin Natural ProductsYu, Shuai; Oh, Jedo; Li, Feng; Kwon, Yongseok; Cho, Hyunkyung; Shin, Jongheon; Lee, Sang Kook; Kim, SangheeACS Medicinal Chemistry Letters (2017), 8 (10), 1066-1071CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)The structure of wondonin marine natural products was renovated to attain new drug-like scaffolds. Wondonins have novel antiangiogenic properties without overt cytotoxicity. However, the chem. instability and synthetic complexity of wondonins have hindered their development as a new type of antiangiogenesis agent. Using a structure-based bioisosterism, the benzodioxole moiety was changed to benzothiazole, and the imidazole moiety was replaced by 1,2,3-triazole. The authors' efforts resulted in a new scaffold with enhanced antiangiogenic activity and minimized cytotoxicity. One compd. with this scaffold effectively inhibited hyaloid vessel formation in diabetic retinopathy mimic zebrafish model. The biol. findings together suggested the potential of the scaffold as a lead structure for development of antiangiogenic drugs with novel functions and as a probe to elucidate new biol. mechanisms assocd. with angiogenesis.(b) Huang, Z.; Williams, R. B.; Martin, S. M.; Lawrence, J. A.; Norman, V. L.; O’Neil-Johnson, M.; Harding, J.; Mangette, J. E.; Liu, S.; Guzzo, P. R.; Starks, C. M.; Eldridge, G. R. Bifidenone: structure-activity relationship and advanced preclinical candidate. J. Med. Chem. 2018, 61, 6736– 6747, DOI: 10.1021/acs.jmedchem.7b01644[ACS Full Text.], [CAS], Google Scholar9bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtlSmurrL&md5=92c58d29301a57d2567bf6a7918800f8Bifidenone: Structure-Activity Relationship and Advanced Preclinical CandidateHuang, Zhongping; Williams, Russell B.; Martin, Steven M.; Lawrence, Julie A.; Norman, Vanessa L.; ONeil-Johnson, Mark; Harding, Jim; Mangette, John E.; Liu, Shuang; Guzzo, Peter R.; Starks, Courtney M.; Eldridge, Gary R.Journal of Medicinal Chemistry (2018), 61 (15), 6736-6747CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Bifidenone is a novel natural tubulin polymn. inhibitor that exhibits antiproliferative activity against a range of human cancer cell lines, making it an attractive candidate for development. A synthetic route was previously developed to alleviate supply constraints arising from its isolation in microgram quantities from a Gabonese tree. Using that previously published route, the authors present here 42 analogs that were synthesized to examine the structure-activity relationship of bifidenone derivs. In addn. to in vitro cytotoxicity data, data from murine xenograft and pharmacokinetic studies were used to evaluate the analogs. Compds. 45b ((6S,7aR)-6-allyl-7a-[(R)-1-(2,5-difluoro-4-methoxyphenyl)propan-2-yl]-7,7a-dihydrobenzo[d][1,3]dioxol-5(6H)-one) and 46b ((6S,7aR)-6-allyl-7a-[(R)-1-(2-fluoro-5-hydroxy-4-methoxyphenyl)propan-2-yl]-7,7a-dihydrobenzo[d][1,3]dioxol-5(6H)-one) were found to demonstrate promising efficacy in murine xenograft expts., and 46b had significantly more potent in vitro antiproliferative activity against taxane-resistant cell lines compared to that of paclitaxel.(c) Corey, E. J.; Wu, Y-. J. Total synthesis of (±)-paeoniflorigenin and paeoniflorin. J. Am. Chem. Soc. 1993, 115, 8871– 8872, DOI: 10.1021/ja00072a063[ACS Full Text.], [CAS], Google Scholar9chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXjtFSntQ%253D%253D&md5=a8087825354cbe383f00d325c7eab2efTotal synthesis of (±)-paeoniflorigenin and paeoniflorinCorey, E. J.; Wu, Yong JinJournal of the American Chemical Society (1993), 115 (19), 8871-2CODEN: JACSAT; ISSN:0002-7863.The first total synthesis of (±)-paeniflorigenin the aglycon of paeoniflorin (I) and I itself has been accomplished.(d) Aicher, T. D.; Buszek, K. R.; Fang, F. G.; Forsyth, C. J.; Jung, S. H.; Kishi, Y.; Matelich, M. C.; Scola, P. M.; Spero, D. M.; Yoon, S. K. Total synthesis of halichondrin B and norhalichondrin B. J. Am. Chem. Soc. 1992, 114, 3162– 3164, DOI: 10.1021/ja00034a086[ACS Full Text.], [CAS], Google Scholar9dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK38XitlGgs7k%253D&md5=46522121b99caecee139b497c2a5e352Total synthesis of halichondrin B and norhalichondrin BAicher, Thomas D.; Buszek, Keith R.; Fang, Francis G.; Forsyth, Craig J.; Jung, Sun Ho; Kishi, Yoshito; Matelich, Michael C.; Scola, Paul M.; Spero, Denice M.; Yoon, Suk KyoonJournal of the American Chemical Society (1992), 114 (8), 3162-4CODEN: JACSAT; ISSN:0002-7863.The first total syntheses of the title compds.(I and II resp.) have been accomplished. These syntheses have established unambiguously the relative and abs. stereochemistry of I and II.(e) Fattorusso, C.; Persico, M.; Calcinai, B.; Cerrano, C.; Parapini, S.; Taramelli, D.; Novellino, E.; Romano, A.; Scala, F.; Fattorusso, E.; Taglialatela-Scafati, O. Manadoperoxides A-D from the Indonesian sponge Plakortis cfr. simplex. Further insights on the structure-activity relationships of simple 1,2-dioxane antimalarials. J. Nat. Prod. 2010, 73, 1138– 1145, DOI: 10.1021/np100196b[ACS Full Text.], [CAS], Google Scholar9ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXmvFaksL0%253D&md5=08a19ee02ba140011edab787728d0505Manadoperoxides A-D from the Indonesian Sponge Plakortis cfr. simplex. Further Insights on the Structure-Activity Relationships of Simple 1,2-Dioxane AntimalarialsFattorusso, Caterina; Persico, Marco; Calcinai, Barbara; Cerrano, Carlo; Parapini, Silvia; Taramelli, Donatella; Novellino, Ettore; Romano, Adriana; Scala, Fernando; Fattorusso, Ernesto; Taglialatela-Scafati, OrazioJournal of Natural Products (2010), 73 (6), 1138-1145CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)The new endoperoxyketal polyketides manadoperoxides A-D (I-IV) were isolated from the Indonesian sponge Plakortis cfr. simplex and their stereostructures established by means of spectroscopic data and semisynthetic transformations. Manadoperoxides were assayed in vitro against D10 and W2 strains of Plasmodium falciparum and showed moderate antimalarial activity compared to that of plakortin and peroxyplakoric B3 ester, the latter differing from manadoperoxide B only by minor structural details. This unexpected difference in the antimalarial activity has been rationalized on the basis of our recently published model for the interaction of 1,2-dioxanes with heme and prodn. of C-centered radicals toxic to the parasite. For the manadoperoxides, either the endoperoxide linkage is inaccessible to the heme iron or the O1 radical cannot evolve to produce a C-centered radical.(f) Chevallier, O. P.; Graham, S. F.; Alonso, E.; Duffy, C.; Silke, J.; Campbell, K.; Botana, L. M.; Elliott, C. T. New insights into the causes of human illness due to consumption of azaspiracid contaminated shellfish. Sci. Rep. 2015, 5, 9818, DOI: 10.1038/srep09818[Crossref], [PubMed], [CAS], Google Scholar.9fhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFOjtbjE&md5=464529d1244b8fa52e82cc9c3f69ad8fNew insights into the causes of human illness due to consumption of azaspiracid contaminated shellfishChevallier, O. P.; Graham, S. F.; Alonso, E.; Duffy, C.; Silke, J.; Campbell, K.; Botana, L. M.; Elliott, C. T.Scientific Reports (2015), 5 (), 9818CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)Azaspiracid (AZA) poisoning was unknown until 1995 when shellfish harvested in Ireland caused illness manifesting by vomiting and diarrhoea. Further in vivo/vitro studies showed neurotoxicity linked with AZA exposure. However, the biol. target of the toxin which will help explain such potent neurol. activity is still unknown. A region of Irish coastline was selected and shellfish were sampled and tested for AZA using mass spectrometry. An outbreak was identified in 2010 and samples collected before and after the contamination episode were compared for their metabolite profile using high resoln. mass spectrometry. Twenty eight ions were identified at higher concn. in the contaminated samples. Stringent bioinformatic anal. revealed putative identifications for seven compds. including, glutarylcarnitine, a glutaric acid metabolite. Glutaric acid, the parent compd. linked with human neurol. manifestations was subjected to toxicol. investigations but was found to have no specific effect on the sodium channel (as was the case with AZA). However in combination, glutaric acid (1mM) and azaspiracid (50nM) inhibited the activity of the sodium channel by over 50%. Glutaric acid was subsequently detected in all shellfish employed in the study. For the first time a viable mechanism for how AZA manifests itself as a toxin is presented.(g) Allan, K.; Stoltz, B. M. A concise total synthesis of (−)-quinocarcin via aryne annulation. J. Am. Chem. Soc. 2008, 130, 17270– 17271, DOI: 10.1021/ja808112y[ACS Full Text.], [CAS], Google Scholar9ghttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsVyhs7%252FM&md5=e8c16616481b4a7be5e46d8f45d11b2aA Concise Total Synthesis of (-)-Quinocarcin via Aryne AnnulationAllan, Kevin M.; Stoltz, Brian M.Journal of the American Chemical Society (2008), 130 (51), 17270-17271CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)A rapid asym. total synthesis of the tetrahydroisoquinoline antitumor antibiotic (-)-quinocarcin (I) was described. The sequence employed a mild fluoride-induced aryne annulation to build a key isoquinoline-contg. intermediate comprising the entire carbon scaffold of the natural product. This intermediate was advanced through six addnl. steps to the target alkaloid, providing the shortest synthetic route to (-)-quinocarcin reported to date.(h) Feng, X.; Bello, D.; Lowe, P. T.; Clark, J.; O’Hagan, D. Two 30-O-β-glucosylated nucleoside fluorometabolites related to nucleocidin in Streptomyces calvus. Chem. Sci. 2019, 10, 9501– 9505, DOI: 10.1039/C9SC03374B[Crossref], [PubMed], [CAS], Google Scholar.9hhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhs1Sgtb3M&md5=5f1728a9b710facb6b5dd7435f2c709dTwo 3'-O-β-glucosylated nucleoside fluorometabolites related to nucleocidin in Streptomyces calvusFeng, Xuan; Bello, Davide; Lowe, Phillip T.; Clark, Joshua; O'Hagan, DavidChemical Science (2019), 10 (41), 9501-9505CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)The antibiotic nucleocidin is a product of the soil bacterium Streptomyces calvus T-3018. It is among the very rare fluorine contg. natural products but is distinct from the other fluorometabolites in that it is not biosynthesised from 5'-fluorodeoxyadenosine via the fluorinase. It seems to have a unique enzymic fluorination process. We disclose here the structures of two 4'-fluoro-3'-O-β-glucosylated metabolites (F-Mets I and II) which appear and then disappear before nucleocidin prodn. in batch cultures of S. calvus. Full genome sequencing of S. calvus T-3018 and an anal. of the putative biosynthetic gene cluster for nucleocidin identified UDP-glucose dependent glucosyl transferase (nucGT) and glucosidase (nucGS) genes within the cluster. We demonstrate that these genes express enzymes that have the capacity to attach and remove glucose from the 3'-O-position of adenosine analogs. In the case of F-Met II, deglucosylation with the NucGS glucosidase generates nucleocidin suggesting a role in its biosynthesis. Gene knockouts of nucGT abolished nucelocidin prodn.(i) Whitley, R.; Alford, C.; Hess, F.; Buchanan, R. Vidarabine: a preliminary review of its pharmacological properties and therapeutic use. Drugs 1980, 20, 267– 282, DOI: 10.2165/00003495-198020040-00002[Crossref], [PubMed], [CAS], Google Scholar.9ihttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL3M%252FitlOmtA%253D%253D&md5=8e68ff27c0178f950bf13dc88df3ae5eVidarabine: a preliminary review of its pharmacological properties and therapeutic useWhitley R; Alford C; Hess F; Buchanan RDrugs (1980), 20 (4), 267-82 ISSN:0012-6667.Vidarabine is the first drug to become generally available in the USA for parenteral treatment of life-threatening or debilitating herpes simplex virus infections of man. For the past decade laboratory and clinical studies have been in progress to assess the pharmacology of the compound, its mechanism of action and its potential usefulness in clinical investigations. Currently, clinical usefulness has been established for herpes simplex infections of the eye and brain. Further studies in progress are evaluating the drug's ability to prevent progressive disease from herpes zoster in the immunocompromised patient, reduce mortality and morbidity from neonatal herpes simplex virus infection and improve outcome of chronic hepatitis B infection.(j) Mazumder, A.; Dwivedi, A.; du Plessis, J. Sinigrin and its therapeutic benefits. Molecules 2016, 21, 416, DOI: 10.3390/molecules21040416[Crossref], [PubMed], [CAS], Google Scholar.9jhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhs12rsLbI&md5=4503bd384eab808d509add5a8b1b9370Sinigrin and its therapeutic benefitsMazumder, Anisha; Dwivedi, Anupma; du Plessis, JeanettaMolecules (2016), 21 (4), 416/1-416/11CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)Sinigrin (allyl-glucosinolate or 2-propenyl-glucosinolate) is a natural aliph. glucosinolate present in plants of the Brassicaceae family, such as broccoli and brussels sprouts, and the seeds of Brassica nigra (mustard seeds) which contain high amts. of sinigrin. Since ancient times, mustard has been used by mankind for its culinary, as well as medicinal, properties. It has been systematically described and evaluated in the classical Ayurvedic texts. Studies conducted on the pharmacol. activities of sinigrin have revealed anti-cancer, antibacterial, antifungal, antioxidant, anti-inflammatory, wound healing properties and biofumigation. This current review will bring concise information about the known therapeutic activities of sinigrin. However, the information on known biol. activities is very limited and, hence, further studies still need to be conducted and its mol. mechanisms also need to be explored. This review on the therapeutic benefits of sinigrin can summarize current knowledge about this unique phytocompounds.(k) Kim, C. S.; Oh, J.; Subedi, L.; Kim, S. Y.; Choi, S. U.; Lee, K. R. Rare thioglycosides from the roots of Wasabia japonica. J. Nat. Prod. 2018, 81, 2129– 2133, DOI: 10.1021/acs.jnatprod.8b00570[ACS Full Text.], [CAS], Google Scholar9khttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhslCiurbL&md5=af67dd71f1af4fb9636267be93747ca1Rare Thioglycosides from the Roots of Wasabia japonicaKim, Chung Sub; Oh, Joonseok; Subedi, Lalita; Kim, Sun Yeou; Choi, Sang Un; Lee, Kang RoJournal of Natural Products (2018), 81 (9), 2129-2133CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)Six new thioglycosides (1-6) were characterized from the roots of W. japonica along with a known analog (7). Of these compds., 1-3 possessed a disulfide bridge connecting the carbohydrate motif and the aglycon, which is extremely rare in Nature. In particular, compd. 1 formed an unusual 1,4,5-oxadithiocane ring system. The structures of the isolated compds. were detd. through conventional NMR and HRMS data anal. procedure, and computational methods with advanced statistics were used for the configurational assignments of 1 and two pairs of inseparable epimers, 2/3 and 4/5. All compds. were evaluated for their anti-inflammatory, neuroprotective, and cytotoxic activities, with 1 showing weak anti-inflammatory activity (IC50 = 41.2 μM).(l) Igarashi, Y.; Asano, D.; Sawamura, M.; In, Y.; Ishida, T.; Imoto, M. Ulbactins F and G, polycyclic thiazoline derivatives with tumor cell migration inhibitory activity from Brevibacillus sp. Org. Lett. 2016, 18, 1658– 1661, DOI: 10.1021/acs.orglett.6b00531[ACS Full Text.], [CAS], Google Scholar9lhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XksV2msro%253D&md5=0f15e5e489c568fd1ff9ec389a655473Ulbactins F and G, polycyclic thiazoline derivatives with tumor cell migration inhibitory activity from Brevibacillus sp.Igarashi, Yasuhiro; Asano, Daisuke; Sawamura, Masashi; In, Yasuko; Ishida, Toshimasa; Imoto, MasayaOrganic Letters (2016), 18 (7), 1658-1661CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)Two new structurally unique compds. bearing a nitrogen- and sulfur-contg. tricyclic ring system, ulbactin F (I) and its diastereomeric isomer ulbactin G (II), were isolated from the culture ext. of a sponge-derived Brevibacillus sp. The structures and abs. configurations of I and II were detd. by NMR anal. and X-ray crystallog. anal. These compds. inhibit the migration of tumor cells in the submicromolar to micromolar range.(m) Iwasa, E.; Hamashima, Y.; Fujishiro, S.; Higuchi, E.; Ito, A.; Yoshida, M.; Sodeoka, M. Total synthesis of (+)-chaetocin and its analogues: their histone methyltransferase G9a inhibitory activity. J. Am. Chem. Soc. 2010, 132, 4078– 4079, DOI: 10.1021/ja101280p[ACS Full Text.], [CAS], Google Scholar9mhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXivVOgtbg%253D&md5=cae6c5ac86d28076e8b8988f8932e7acTotal Synthesis of (+)-Chaetocin and its Analogues: Their Histone Methyltransferase G9a Inhibitory ActivityIwasa, Eriko; Hamashima, Yoshitaka; Fujishiro, Shinya; Higuchi, Eisuke; Ito, Akihiro; Yoshida, Minoru; Sodeoka, MikikoJournal of the American Chemical Society (2010), 132 (12), 4078-4079CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)The first total synthesis of (+)-chaetocin (I) has been accomplished in nine steps starting from known N-Cbz-N-Me-serine using radical α-bromination reaction and Co(I)-mediated reductive dimerization reaction as key reactions. The enantiomers show comparable inhibitory activity toward histone methyltransferase (HMT) G9a, but analogs without the sulfur functionality are inactive.(n) Zipperer, A.; Konnerth, M.; Laux, C.; Berscheid, A.; Janek, D.; Weidenmaier, C.; Burian, M.; Schilling, N. A.; Slavetinsky, C.; Marschal, M.; Willmann, M.; Kalbacher, H.; Schittek, B.; Brötz-Oesterhelt, H.; Grond, S.; Peschel, A.; Krismer, B. Human commensals producing a novel antibiotic impair pathogen colonization. Nature 2016, 535, 511– 516, DOI: 10.1038/nature18634[Crossref], [PubMed], [CAS], Google Scholar.9nhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xht1Ont73P&md5=04c4e8b4dac5aa1c56edf164e8360a3dHuman commensals producing a novel antibiotic impair pathogen colonizationZipperer, Alexander; Konnerth, Martin C.; Laux, Claudia; Berscheid, Anne; Janek, Daniela; Weidenmaier, Christopher; Burian, Marc; Schilling, Nadine A.; Slavetinsky, Christoph; Marschal, Matthias; Willmann, Matthias; Kalbacher, Hubert; Schittek, Birgit; Broetz-Oesterhelt, Heike; Grond, Stephanie; Peschel, Andreas; Krismer, BernhardNature (London, United Kingdom) (2016), 535 (7613), 511-516CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)Nasal Staphylococcus lugdunensis strains produce lugdunin, a novel thiazolidine-contg. cyclic peptide antibiotic that prohibits colonization by Staphylococcus aureus, and a rare example of a non-ribosomally synthesized bioactive compd. from human-assocd. bacteria. Lugdunin is bactericidal against major pathogens, effective in animal models, and not prone to causing development of resistance in S. aureus. Notably, human nasal colonization by S. lugdunensis was assocd. with a significantly reduced S. aureus carriage rate, suggesting that lugdunin or lugdunin-producing commensal bacteria could be valuable for preventing staphylococcal infections. Moreover, human microbiota should be considered as a source for new antibiotics.(o) Foo, K.; Newhouse, T.; Mori, I.; Takayama, H.; Baran, P. S. Total synthesis guided structure elucidation of (+)-psychotetramine. Angew. Chem., Int. Ed. 2011, 50, 2716– 2719, DOI: 10.1002/anie.201008048[Crossref], [CAS], Google Scholar.9ohttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXivVGhtbc%253D&md5=9f6c0fa7f5dea05af6706a4c424613cdTotal Synthesis Guided Structure Elucidation of (+)-PsychotetramineFoo, Klement; Newhouse, Timothy; Mori, Ikue; Takayama, Hiromitsu; Baran, Phil S.Angewandte Chemie, International Edition (2011), 50 (12), 2716-2719, S2716/1-S2716/61CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)The title compd. I was prepd. and its structure was solved. The pursuit of this complex natural product also led to an efficient enantioselective synthesis of the related alkaloid (+)-psychotrimine II, an improved procedure for direct-indole aniline coupling, and one of the most complex and demanding contexts for a Buchwald-Hartwig amination.(p) Ohyabu, N.; Nishikawa, T.; Isobe, M. First asymmetric total synthesis of tetrodotoxin. J. Am. Chem. Soc. 2003, 125, 8798– 8805, DOI: 10.1021/ja0342998[ACS Full Text], [CAS], Google Scholar9phttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXkvFWlsr4%253D&md5=cd58508c4ad88a86568810133281fe64First Asymmetric Total Synthesis of TetrodotoxinOhyabu, Norio; Nishikawa, Toshio; Isobe, MinoruJournal of the American Chemical Society (2003), 125 (29), 8798-8805CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Tetrodotoxin, a toxic principle of puffer fish poisoning, is one of the most famous marine natural products because of the complex structure having many functional groups and its potent biol. activity leading to death. Since the structure elucidation in 1964, this toxin has been recognized as a formidable target mol. for total synthesis. We have recently achieved the first asym. total synthesis from 2-acetoxy-tri-O-acetyl-D-glucal as a chiral starting material. The highly hydroxylated cyclohexane ring was constructed by Claisen rearrangement and regioselective hydroxylations of an acetone moiety and an intramol. directed aldol condensation of the precursor having Me ketone with dihydroxyacetone, which was synthesized through Sonogashira coupling. Installation of nitrogen functionality was unsuccessful through an attempted Overman rearrangement. We, therefore, employed a new intramol. conjugate addn. strategy between the carbamate and unsatd. ester groups. The α-hydroxyl lactone moiety was synthesized through an intramol. epoxide opening by the Z-enolate of aldehyde, which was followed by oxidn.-redn. of the resulting cyclic vinyl ether. The lactone was then converted to a protected ortho ester, and then gunanidinylation was followed by cleavage of the 1,2-glycol to give the fully protected tetrodotoxin. Selection of the protective groups has finally led us to accomplish the total synthesis of tetrodotoxin in an enantiomerically pure form. All the stereogenic centers were controlled with high selectivity, and the hydroxyl groups were differently protected to discriminate for the future analog synthesis of a bioorg. program. The synthetic tetrodotoxin was purified by ion exchange chromatog. and characterized to be identical with the natural compd.
- 10(a) Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell, N. A. Applications of fluorine in medicinal chemistry. J. Med. Chem. 2015, 58, 8315– 8359, DOI: 10.1021/acs.jmedchem.5b00258[ACS Full Text.], [CAS], Google Scholar10ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1ajs7%252FK&md5=9995829a94a8c0b8d9fb0d21bdfd5a1dApplications of Fluorine in Medicinal ChemistryGillis, Eric P.; Eastman, Kyle J.; Hill, Matthew D.; Donnelly, David J.; Meanwell, Nicholas A.Journal of Medicinal Chemistry (2015), 58 (21), 8315-8359CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review with meta-anal. The role of fluorine in drug design and development is expanding rapidly as we learn more about the unique properties assocd. with this unusual element and how to deploy it with greater sophistication. The judicious introduction of fluorine into a mol. can productively influence conformation, pKa, intrinsic potency, membrane permeability, metabolic pathways, and pharmacokinetic properties. In addn., 18F has been established as a useful positron emitting isotope for use with in vivo imaging technol. that potentially has extensive application in drug discovery and development, often limited only by convenient synthetic accessibility to labeled compds. The wide ranging applications of fluorine in drug design are providing a strong stimulus for the development of new synthetic methodologies that allow more facile access to a wide range of fluorinated compds. In this review, we provide an update on the effects of the strategic incorporation of fluorine in drug mols. and applications in positron emission tomog.(b) Meanwell, N. A. Fluorine and fluorinated motifs in the design and application of bioisosteres for drug design. J. Med. Chem. 2018, 61, 5822– 5880, DOI: 10.1021/acs.jmedchem.7b01788[ACS Full Text.], [CAS], Google Scholar10bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitV2qu7w%253D&md5=2d0ce3326c7ff932da8d7d26972ced14Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug DesignMeanwell, Nicholas A.Journal of Medicinal Chemistry (2018), 61 (14), 5822-5880CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The electronic properties and relatively small size of fluorine endow it with considerable versatility as a bioisostere and it has found application as a substitute for lone pairs of electrons, the hydrogen atom, and the Me group while also acting as a functional mimetic of the carbonyl, carbinol, andnitrile moieties. In this context, fluorine substitution can influence the potency, conformation, metab., membrane permeability, and P-gp recognition of a mol. and temper inhibition of the hERG channel by basic amines. However, as a consequence of the unique properties of fluorine, it features prominently in the design of higher order structural metaphors that are more esoteric in their conception and which reflect a more sophisticated mol. construction that broadens biol. mimesis. In this Perspective, applications of fluorine in the construction of bioisosteric elements designed to enhance the in vitro and in vivo properties of a mol. are summarized.(c) Liu, B.; Thayumanavan, S. Substituent effects on the pH sensitivity of acetals and ketals and their correlation with encapsulation stability in polymeric nanogels. J. Am. Chem. Soc. 2017, 139, 2306– 2317, DOI: 10.1021/jacs.6b11181[ACS Full Text], [CAS], Google Scholar10chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsVagt78%253D&md5=b265a1435bcc42b4fce000034d13d279Substituent Effects on the pH Sensitivity of Acetals and Ketals and Their Correlation with Encapsulation Stability in Polymeric NanogelsLiu, Bin; Thayumanavan, S.Journal of the American Chemical Society (2017), 139 (6), 2306-2317CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)The effect of structural variations in acetal- and ketal-based linkers upon their degrdn. kinetics is studied through the design, synthesis, and study of six series of mols., comprising a total of 18 different mols. Through this systematic study, the structural fine-tuning of the linkers allows access to variations in kinetics of degrdn. of >6 orders of magnitude. Hammett correlations show that the ρ value for the hydrolysis of benzylidene acetals is ∼-4.06, which is comparable to an SN1-like process. There is a strong, developing pos. charge at the benzylic position in the transition state during the degrdn. of acetals. This pos. charged transition state is consistent with the relative degrdn. rates of acetals vs. ketals (correlated to stabilities of 1°, 2°, and 3° carboxonium ion type intermediates) and the obsd. effect of proximal electron-withdrawing groups upon the degrdn. rates. Following this, the authors studied whether the degrdn. kinetics study correlates with pH-sensitive variations in the host-guest characteristics of polymeric nanogels that contains these acetal or ketal moieties as crosslinking functionalities. Indeed, the trends obsd. in the small mol. degrdn. have clear correlations with the encapsulation stability of guest mols. within these polymeric nanogels. The implications of this fundamental study extend to a broad range of applications, well beyond the polymeric nanogel examples studied here.
- 11(a) Gillies, E. R.; Goodwin, A. P.; Fréchet, J. M. Acetals as pH-sensitive linkages for drug delivery. Bioconjugate Chem. 2004, 15, 1254– 1263, DOI: 10.1021/bc049853x[ACS Full Text.], [CAS], Google Scholar11ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXotlartbY%253D&md5=e9a5cb11f2b4130753c53742b8ed1783Acetals as pH-sensitive linkages for drug deliveryGillies, Elizabeth R.; Goodwin, Andrew P.; Frechet, Jean M. J.Bioconjugate Chemistry (2004), 15 (6), 1254-1263CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)PH-sensitive linkages designed to undergo hydrolysis at mildly acidic pH can trigger the release of therapeutics selectively at targets such as tumor and inflammatory tissues and in the endosomes and lysosomes of cells. Acetals have the potential to be used as linkages for a range of alc. functionalities, and, by altering their chem. structure, it is possible to tune their hydrolysis rate. The synthesis of four conjugates of model drug mols. with PEO using acetals of varying chem. structure were described herein. Primary and secondary alcs., as well as syn-1,2-diols, were incorporated in the conjugates. The hydrolysis kinetics were investigated by HPLC, and the conjugates had half-lives ranging from less than 1 min to several days at pH 5.0, with slower hydrolysis at pH 7.4 in all cases. These acetal linkages were therefore promising for use in a variety of drug delivery applications ranging from polymer-drug conjugates to pH-sensitive micelles and nanoparticulate systems.(b) Gillies, E. R.; Fréchet, J. M. pH-Responsive copolymer assemblies for controlled release of doxorubicin. Bioconjugate Chem. 2005, 16, 361– 368, DOI: 10.1021/bc049851c[ACS Full Text.], [CAS], Google Scholar11bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtF2jsL8%253D&md5=fd200f7d1acbf478e52e2ad5179e1673pH-responsive copolymer assemblies for controlled release of doxorubicinGillies, Elizabeth R.; Frechet, Jean M. J.Bioconjugate Chemistry (2005), 16 (2), 361-368CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)PH-Responsive drug carriers have the potential to provide selective drug release at therapeutic targets including tumors and in acidic intracellular vesicles such as endosomes and lysosomes. We have developed a new approach to the design of acid-sensitive micelles by incorporating hydrophobic acetal groups on the core block of a micelle-forming block copolymer. Hydrolysis of the acetals at mildly acidic pH is designed to reveal polar groups on the core-forming block, thus changing its soly. and disrupting the micelle, triggering drug release. The anticancer drug doxorubicin (DOX) was encapsulated in these pH-sensitive micelles, and the acetal hydrolysis rates and DOX release rates were detd. in the pH range of 4.0 to 7.4 and were compared to those of control systems. The micelle disruption was investigated by dynamic light scattering. The in vitro toxicities of the empty and DOX-loaded micelles were detd., and the intracellular fate of the encapsulated DOX was compared to free DOX using fluorescence confocal microscopy.(c) Huang, F.; Cheng, R.; Meng, F.; Deng, C.; Zhong, Z. Micelles based on acid degradable poly(acetal urethane): preparation, pH-sensitivity, and triggered intracellular drug release. Biomacromolecules 2015, 16, 2228– 2236, DOI: 10.1021/acs.biomac.5b00625[ACS Full Text.], [CAS], Google Scholar11chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVOit73O&md5=b8de89a45212089b9bf33aea95f20aa5Micelles Based on Acid Degradable Poly(acetal urethane): Preparation, pH-Sensitivity, and Triggered Intracellular Drug ReleaseHuang, Fushi; Cheng, Ru; Meng, Fenghua; Deng, Chao; Zhong, ZhiyuanBiomacromolecules (2015), 16 (7), 2228-2236CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)Polyurethanes are a unique class of biomaterials that are widely used in medical devices. In spite of their easy synthesis and excellent biocompatibility, polyurethanes are less explored for controlled drug delivery due to their slow or lack of degrdn. In this paper, we report the design and development of novel acid degradable poly(acetal urethane) (PAU) and corresponding triblock copolymer micelles for pH-triggered intracellular delivery of a model lipophilic anticancer drug, doxorubicin (DOX). PAU with Mn ranging from 4.3 to 12.3 kg/mol was conveniently prepd. from polycondensation reaction of lysine diisocyanate (LDI) and a novel diacetal-contg. diol, terephthalilidene-bis(trimethylolethane) (TPABTME) using dibutyltin dilaurate (DBTDL) as a catalyst in N,N-dimethylformamide (DMF). The thiol-ene click reaction of Allyl-PAU-Allyl with thiolated PEG (Mn = 5.0 kg/mol) afforded PEG-PAU-PEG triblock copolymers that readily formed micelles with av. sizes of about 90-120 nm in water. The dynamic light scattering (DLS) measurements revealed fast swelling and disruption of micelles under acidic pH. UV/vis spectroscopy corroborated that acetal degrdn. was accelerated at pH 4.0 and 5.0. The in vitro release studies showed that doxorubicin (DOX) was released in a controlled and pH-dependent manner, in which ca. 96%, 73%, and 30% of drug was released within 48 h at pH 4.0, 5.0, and 7.4, resp. Notably, MTT assays displayed that DOX-loaded PEG-PAU-PEG micelles had a high in vitro antitumor activity in both RAW 264.7 and drug-resistant MCF-7/ADR cells. The confocal microscopy and flow cytometry expts. demonstrated that PEG-PAU-PEG micelles mediated efficient cytoplasmic delivery of DOX. Importantly, blank PEG-PAU-PEG micelles were shown to be nontoxic to RAW 264.7 and MCF-7/ADR cells even at a high concn. of 1.5 mg/mL. Hence, micelles based on poly(acetal urethane) have appeared as a new class of biocompatible and acid-degradable nanocarriers for efficient intracellular drug delivery.(d) Cui, L.; Cohen, J. L.; Chu, C. K.; Wich, P. R.; Kierstead, P. H.; Fréchet, J. M. Conjugation chemistry through acetals toward a dextran-based delivery system for controlled release of siRNA. J. Am. Chem. Soc. 2012, 134, 15840– 15848, DOI: 10.1021/ja305552u[ACS Full Text.], [CAS], Google Scholar11dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhtlaisr3L&md5=e5ba3b8bec76608e7dbb823bf3cd501bConjugation Chemistry through Acetals toward a Dextran-Based Delivery System for Controlled Release of siRNACui, Lina; Cohen, Jessica L.; Chu, Crystal K.; Wich, Peter R.; Kierstead, Paul H.; Frechet, Jean M. J.Journal of the American Chemical Society (2012), 134 (38), 15840-15848CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)New conjugation chem. for polysaccharides, exemplified by dextran, was developed to enable the attachment of therapeutic or other functional moieties to the polysaccharide through cleavable acetal linkages. The acid-lability of the acetal groups allows the release of therapeutics under acidic conditions, such as that of the endocytic compartments of cells, regenerating the original free polysaccharide in the end. The phys. and chem. behavior of these acetal groups can be adjusted by modifying their stereoelectronic and steric properties, thereby providing materials with tunable degrdn. and release rates. We have applied this conjugation chem. in the development of water-sol. siRNA carriers, namely acetal-linked amino-dextrans, with various amine structures attached through either slow- or fast-degrading acetal linker. The carriers with the best combination of amine moieties and structural compn. of acetals showed high in vitro transfection efficiency and low cytotoxicity in the delivery of siRNA.(e) Hong, B. J.; Chipre, A. J.; Nguyen, S. T. Acid-degradable polymer-caged lipoplex (PCL) platform for siRNAdelivery: facile cellular triggered release of siRNA. J. Am. Chem. Soc. 2013, 135, 17655– 17658, DOI: 10.1021/ja404491r[ACS Full Text.], [CAS], Google Scholar11ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtlOktrjE&md5=b7e0f90d673e3bd911ecaa1735a34199Acid-Degradable Polymer-Caged Lipoplex (PCL) Platform for siRNA Delivery: Facile Cellular Triggered Release of siRNAHong, Bong Jin; Chipre, Anthony J.; Nguyen, SonBinh T.Journal of the American Chemical Society (2013), 135 (47), 17655-17658CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)An acid-degradable polymer-caged lipoplex (PCL) platform consisting of a cationic lipoplex core and a biocompatible, pH-responsive polymer shell has been developed for the effective delivery of small interfering RNA (siRNA) through a combination of facile loading, rapid acid-triggered release, cellular internalization, and effective endosomal escape. In vitro testing of this degradable PCL delivery platform reveals ∼45- and ∼2.5-fold enhancement of enhanced green fluorescent protein knockdown in cancer cells in comparison to either free siRNA or siRNA-loaded non-acid-degradable lipoplex formulations, resp.(f) Broaders, K. E.; Cohen, J. A.; Beaudette, T. T.; Bachelder, E. M.; Fréchet, J. M. Acetalated dextran is a chemically and biologically tunable material for particulate immunotherapy. Proc. Natl. Acad. Sci. U. S. A. 2009, 106, 5497– 5502, DOI: 10.1073/pnas.0901592106[Crossref], [PubMed], [CAS], Google Scholar.11fhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXkvFOnsrk%253D&md5=8d04187079deedd36810463a6a613b3cAcetylated dextran is a chemically and biologically tunable material for particulate immunotherapyBroaders, Kyle E.; Cohen, Joel A.; Beaudette, Tristan T.; Bachelder, Eric M.; Frechet, Jean M. J.Proceedings of the National Academy of Sciences of the United States of America (2009), 106 (14), 5497-5502CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Materials that combine facile synthesis, simple tuning of degrdn. rate, processability, and biocompatibility are in high demand for use in biomedical applications. The authors report on acetylated dextran, a biocompatible material that can be formed into microparticles with degrdn. rates that are tunable over 2 orders of magnitude depending on the degree and type of acetal modification. Varying the degrdn. rate produces particles that perform better than poly(lactic-co-glycolic acid) and iron oxide, two commonly studied materials used for particulate immunotherapy, in major histocompatibility complex class, I (MHC I) and MHC II presentation assays. Modulating the material properties leads to antigen presentation on MHC I via pathways that are dependent or independent of the transporter assocd. with antigen processing. To the best of the authors' knowledge, this is the only example of a material that can be tuned to operate on different immunol. pathways while maximizing immunol. presentation.(g) Lee, S.; Wang, W.; Lee, Y.; Sampson, N. S. Cyclic acetals as cleavable linkers for affinity capture. Org. Biomol. Chem. 2015, 13, 8445– 8452, DOI: 10.1039/C5OB01056J[Crossref], [PubMed], [CAS], Google Scholar11ghttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFWgurfF&md5=3d7c45da0e983ec1ab46612af5e85501Cyclic acetals as cleavable linkers for affinity captureLee, Siyeon; Wang, Wei; Lee, Younjoo; Sampson, Nicole S.Organic & Biomolecular Chemistry (2015), 13 (31), 8445-8452CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)Labeling proteins with biotin is a widely used method to identify target proteins due to biotin's strong binding affinity for streptavidin. Combined with alkyne-azide cycloaddn., which enables the coupling of probes to targeted proteins, biotin tags linked to an alkyne or azide have become a powerful tool for purifn. and anal. of proteins in proteomics. However, biotin requires harsh elution conditions to release the captured protein from the bead matrix. Use of these conditions reduces signal to noise and complicates the anal. To improve affinity capture, cleavable linkers have been introduced. Here, the authors demonstrate the use of a cyclic acetal biotin probe that was prepd. easily from com. available starting materials, is stable to cell lysates, yet is cleaved under mildly acidic conditions, and which provides an aldehyde for further elaboration of the protein, if desired.
- 12Maryanoff, B. E. Phenotypic assessment and the discovery of topiramate. ACS Med. Chem. Lett. 2016, 7, 662– 665, DOI: 10.1021/acsmedchemlett.6b00176[ACS Full Text], [CAS], Google Scholar12https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XpsF2mtLc%253D&md5=227d9ac65313ec8a3401393ba4715390Phenotypic Assessment and the Discovery of TopiramateMaryanoff, Bruce E.ACS Medicinal Chemistry Letters (2016), 7 (7), 662-665CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)The role of phenotypic assessment in drug discovery is discussed, along with the discovery and development of TOPAMAX (topiramate), a billion-dollar mol. for the treatment of epilepsy and migraine.
- 13Hale, J. L.; Mills, S. G.; MacCoss, M.; Finke, P. E.; Cascieri, M. A.; Sadowski, S.; Ber, E.; Chicchi, G. G.; Kurtz, M.; Metzger, J.; Eiermann, G.; Tsou, N. N.; Tattersall, F. D.; Rupniak, N. M.; Williams, A. R.; Rycroft, W.; Hargreaves, R.; MacIntyre, D. E. Structural optimization affording2-(R)-(1-(R)-3,5-bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-oxo-1,2,4-triazol-5-yl)methylmorpholine, a potent, orally active, long-acting morpholine acetal human NK-1 receptor antagonist. J. Med. Chem. 1998, 41, 4607– 4614, DOI: 10.1021/jm980299k[ACS Full Text], [CAS], Google Scholar13https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXmtlansrY%253D&md5=0ca98b5fb6a2957deffee22fa62aa988Structural Optimization Affording 2-(R)-(1-(R)-3,5-Bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4- (3-oxo-1,2,4-triazol-5-yl)methylmorpholine, a Potent, Orally Active, Long-Acting Morpholine Acetal Human NK-1 Receptor AntagonistHale, Jeffrey J.; Mills, Sander G.; MacCoss, Malcolm; Finke, Paul E.; Cascieri, Margaret A.; Sadowski, Sharon; Ber, Elzbieta; Chicchi, Gary G.; Kurtz, Marc; Metzger, Joseph; Eiermann, George; Tsou, Nancy N.; Tattersall, F. David; Rupniak, Nadia M. J.; Williams, Angela R.; Rycroft, Wayne; Hargreaves, Richard; MacIntyre, D. EuanJournal of Medicinal Chemistry (1998), 41 (23), 4607-4614CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Structural modifications requiring novel synthetic chem. were made to the morpholine acetal human neurokinin-1 (hNK-1) receptor antagonist L-742694, and this resulted in the discovery of 2-(R)-(1-(R)-3,5-bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-oxo-1,2,4-triazol-5-yl)methyl morpholine (I). This modified compd. is a potent, long-acting hNK-1 receptor antagonist as evidenced by its ability to displace [125I]Substance P from hNK-1 receptors stably expressed in CHO cells (IC50 = 0.09 ± 0.06 nM) and by the measurement of the rates of assocn. (k1 = 2.8 ± 1.1 × 108 M-1 min-1) and dissocn. (k-1 = 0.0054 ± 0.003 min-1) of I from hNK-1 expressed in Sf9 membranes which yields Kd = 19 ± 12 pM and a t1/2 for receptor occupancy equal to 154 ± 75 min. Inflammation in the guinea pig induced by a resiniferatoxin challenge (with NK-1 receptor activation mediating the subsequent increase in vascular permeability) is inhibited in a dose-dependent manner by the oral preadmininstration of I (IC50 (1 h) = 0.008 mg/kg; IC90 (24 h) = 1.8 mg/kg), indicating that this compd. has good oral bioavailability and peripheral duration of action. Central hNK-1 receptor stimulation is also inhibited by the systemic preadministration of I as shown by its ability to block an NK-1 agonist-induced foot tapping response in gerbils (IC50 (4 h) = 0.04 ± 0.006 mg/kg; IC50 (24 h) = 0.33 ± 0.017 mg/kg) and by its antiemetic actions in the ferret against cisplatin challenge. The activity of I at extended time points in these preclin. animal models sets it apart from earlier morpholine antagonists (such as L-742694), and the piperidine antagonists CP 122721 and GR 205171 and could prove to be an advantage in the treatment of chronic disorders related to the actions of Substance P. In part on the basis of these data, I has been identified as a potential clin. candidate for the treatment of peripheral pain, migraine, chemotherapy-induced emesis, and various psychiatric disorders.
- 14Delost, M. D.; Smith, D. T.; Anderson, B. J.; Njardarson, J. T. From oxiranes to oligomers: architectures of U.S. FDA approved pharmaceuticals containing oxygen heterocycles. J. Med. Chem. 2018, 61, 10996– 11020, DOI: 10.1021/acs.jmedchem.8b00876[ACS Full Text], [CAS], Google Scholar14https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtlGit7nE&md5=18f3979c80513bfbbc263dd5945c63f0From Oxiranes to Oligomers: Architectures of U.S. FDA Approved Pharmaceuticals Containing Oxygen HeterocyclesDelost, Michael D.; Smith, David T.; Anderson, Benton J.; Njardarson, Jon T.Journal of Medicinal Chemistry (2018), 61 (24), 10996-11020CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Oxygen heterocycles are the second most common type of heterocycles that appear as structural components of U.S. Food and Drug Administration (FDA) approved pharmaceuticals. Anal. of our database of drugs approved through 2017 reveals 311 distinct pharmaceuticals contg. at least one oxygen heterocycle. Most prevalent among these are pyranoses, with furanoses, macrolactones, morpholines, and dioxolanes rounding off the top five. The main body of this Perspective is organized according to ring size, commencing with three- and four-membered rings and ending with macrocycles, polymers, and unusual oxygen-contg. heterocycles. For each section, all oxygen heterocycle-contg. drugs are presented along with a brief discussion about structural and drug application patterns.
- 15(a) De Wolfe, R. H.; Ivanetich, K. M.; Perry, N. F. General acid catalysis in benzophenone ketal hydrolysis. J. Org. Chem. 1969, 34, 848– 854, DOI: 10.1021/jo01256a015[ACS Full Text.], [CAS], Google Scholar15ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF1MXktFahsL8%253D&md5=7fdcaddba53337826472b32f180e92b7General acid catalysis in benzophenone ketal hydrolysisDe Wolfe, Robert H.; Ivanetich, Kathryn M.; Perry, Noreen F.Journal of Organic Chemistry (1969), 34 (4), 848-54CODEN: JOCEAH; ISSN:0022-3263.Benzophenone diethyl ketal (I), 2,2-diphenyl-1,3-dioxolane, 2,2-bis(p-methoxyphenyl)-1,3-dioxolane, 2,2-di(p-tolyl)-1,3-dioxolane and 2,2-bis-(p-chlorophenyl)-1,3-dioxolane were prepd. and their kinetics of hydrolysis studied in aq. dioxane formate, chloroacetate, and dichloroacetate buffers. General acid catalysis was observed for hydrolysis of ketals of benzophenone, 4,4'-dimenthoxybenzo-phenone, and 4,4'-dimethylbenzophenone in chloroacetate and dichloroacetate buffers. Catalytic coeffs. for the buffer acids and for H+ were derived from the kinetic data. H+ catalytic coeffs. correlate closely with Hammett's substituent consts. for the para substituents. The entropy of activation for H+-catalyzed hydrolysis is near zero for I and slightly neg. for the 2,2-diaryl-1,3-dioxolanes. The relation between acetal and ketal structures and the mechanisms (A1 or SE2) by which they hydrolyze are discussed.(b) Fife, T. H. General acid catalysis of acetal, ketal, and ortho ester hydrolysis. Acc. Chem. Res. 1972, 5, 264– 272, DOI: 10.1021/ar50056a002[ACS Full Text.], [CAS], Google Scholar15bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE38XltVSgtrw%253D&md5=6e5093eaa131da89ec2413dc7ff8f096General acid catalysis of acetal, ketal, and ortho ester hydrolysisFife, Thomas H.Accounts of Chemical Research (1972), 5 (8), 264-72CODEN: ACHRE4; ISSN:0001-4842.The structural features in acetals and ketals that will give rise to general acid catalyzed hydrolysis reactions have been determined. General acid catalysis by buffer acids will be detectable if the leaving group is good (a phenol) and basicity is low in cases where a moderately stable carbonium ion is formed as an intermediate. General acid catalysis will result when the leaving group is poor (an aliphatic alcohol) if the carbonium ion intermediate is exceedingly stable (an alkoxytropylium ion) or if there is great steric strain in the ground state which is relieved in the transition state. Intramolecular general acid catalysis by a substituent carboxyl group is observed with acetals having good leaving groups and giving rise to relatively stable oxo-carbonium ions so that buffer acid catalysis can be detected in hydrolysis of the unsubstituted compounds. In these reactions the efficiency of intra to intermolecular catalysis is quite large, and rate enhancements of 105-109 take place in comparison with suitable derivatives in which carboxyl group participation is not possible. The mechanism of action of lysozyme is discussed from the standpoint of this information.(c) Cordes, E. H.; Bull, H. G. Mechanism and catalysis for hydrolysis of acetals, ketals, and ortho esters. Chem. Rev. 1974, 74, 581– 603, DOI: 10.1021/cr60291a004[ACS Full Text.], [CAS], Google Scholar15chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE2cXlsFWisL4%253D&md5=362eab6033de06eb30dd958a0c221a79Mechanism and catalysis for hydrolysis of acetals, ketals, and ortho estersCordes, E. H.; Bull, H. G.Chemical Reviews (Washington, DC, United States) (1974), 74 (5), 581-603CODEN: CHREAY; ISSN:0009-2665.A review with 99 refs.(d) Wasserman, H. H.; Clark, G. M.; Turley, P. C. Recent aspects of cyclopropanone chemistry. In: Stereochemistry I. Topics in Current Chemistry Fortschritte der Chemischen Forschung 1974, 47, 73– 156, DOI: 10.1007/3-540-06648-9_9[Crossref], [CAS], Google Scholar.15dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE2cXkvFWjur4%253D&md5=f79e09ef0a01614705031245c4cc70ceRecent aspects of cyclopropanone chemistryWasserman, Harry H.; Clark, George M.; Turley, Patricia C.Topics in Current Chemistry (1974), 47 (), 73-156CODEN: TPCCAQ; ISSN:0340-1022.A review with 140 refs.(e) Deslongchamps, P.; Dory, Y. L.; Li, S. The relative rate of hydrolysis of a series of acyclic and six-membered cyclic acetals, ketals, orthoesters, and orthocarbonates. Tetrahedron 2000, 56, 3533– 3537, DOI: 10.1016/S0040-4020(00)00270-2[Crossref], [CAS], Google Scholar.15ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXjvFOqtbg%253D&md5=e748b95ddb87192eea8b186ba929e239The relative rate of hydrolysis of a series of acyclic and six-membered cyclic acetals, ketals, orthoesters, and orthocarbonatesDeslongchamps, Pierre; Dory, Yves L.; Li, ShiguiTetrahedron (2000), 56 (22), 3533-3537CODEN: TETRAB; ISSN:0040-4020. (Elsevier Science Ltd.)The relative rate of hydrolysis of these compds. is rationalized by considering the influence of steric, inductive and stereo-electronic effects on the hydrolysis reaction mechanism.(f) Li, S.; Dory, Y. L.; Deslongchamps, P. On the relative rate of hydrolysis of a series of ketals and their proton affinities. Isr. J. Chem. 2000, 40, 209– 215, DOI: 10.1560/QRH5-Q3N0-0XA6-PT9Y[Crossref], [CAS], Google Scholar.15fhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXlsVCktrc%253D&md5=72f0c2ac31bf5bb5bd5706b97161ee49On the relative rate of hydrolysis of a series of ketals and their proton affinitiesLi, Shigui; Dory, Yves L.; Deslongchamps, PierreIsrael Journal of Chemistry (2000), 40 (3-4), 209-215CODEN: ISJCAT; ISSN:0021-2148. (Laser Pages Publishing)The relative rates of hydrolysis of cyclic and acyclic ketals were studied. Their reactivity toward acid hydrolysis is explained by considering the ease of protonation and the cleavage of the C-O bond. The exptl. work and the theor. calcns. of the proton affinities of the ketals suggest that the rate-limiting step of hydrolysis of ketals is a concerted protonation and cleavage of the C-O bond. The relative proton affinity is considered to be a direct consequence of the ease of proper lone pair orbital alignment on the O atoms of the various ketals.(g) Repetto, S. L.; Costello, J. F.; Butts, C. P.; Lam, J. K. W.; Ratcliffe, N. M. The hydrolysis of geminal ethers: a kinetic appraisal of orthoesters and ketals. Beilstein J. Org. Chem. 2016, 12, 1467– 1475, DOI: 10.3762/bjoc.12.143[Crossref], [PubMed], [CAS], Google Scholar.15ghttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslKjtbnP&md5=423ed1261e2ea6ebe3f8ddd4cdce2807The hydrolysis of geminal ethers: a kinetic appraisal of orthoesters and ketalsRepetto, Sonia L.; Costello, James F.; Butts, Craig P.; Lam, Joseph K. W.; Ratcliffe, Norman M.Beilstein Journal of Organic Chemistry (2016), 12 (), 1467-1475CODEN: BJOCBH; ISSN:1860-5397. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)A novel approach to protecting jet fuel against the effects of water contamination is predicated upon the coupling of the rapid hydrolysis reactions of lipophilic cyclic geminal ethers, with the concomitant prodn. of a hydrophilic acyclic hydroxyester with de-icing properties (Fuel Dehydrating Icing Inhibitors - FDII). To this end, a kinetic appraisal of the hydrolysis reactions of representative geminal ethers was undertaken using a convenient surrogate for the fuel-water interface (D2O/CD3CN 1:4). We present here a library of acyclic and five/six-membered cyclic geminal ethers arranged according to their hydroxonium catalytic coeffs. for hydrolysis, providing for the first time a framework for the development of FDII. A combination of 1H NMR, labeling and computational studies was used to assess the effects that may govern the obsd. relative rates of hydrolyzes.(h) Salomaa, P.; Kankaanpera, A.; Norin, T. The hydrolysis of 1,3-dioxolan and its alkyl-substituted derivatives. Part I. the structural factors influencing the rates of hydrolysis of a series of methyl-substituted dioxolans. Acta Chem. Scand. 1961, 15, 871– 878, DOI: 10.3891/acta.chem.scand.15-0871[Crossref], [CAS], Google Scholar.15hhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF38XksV2huro%253D&md5=05e33d8429eaa0c3314c051bc00d1749Hydrolysis of 1,3-dioxolane and its alkyl-substituted derivatives. I. Structural factors influencing the rates of hydrolysis of a series of methyl-substituted dioxolanesSalomaa, Pentti; Kankaanpera, AlpoActa Chemica Scandinavica (1961), 15 (), 871-8CODEN: ACHSE7; ISSN:0904-213X.The exptl. techniques for the rate studies were dilatometric, for dioxolane derivs. which carried one or two Me groups at the 2-position, and titrimetric, for those derivs. that did not carry substituents at the 2-position. Based on the magnitude of the activation entropies, it was probable that the dioxolanes hydrolyzed by essentially the same mechanism as acyclic acetals. The introduction of a methyl group at the 2-position increased the rate of hydrolysis of dioxolanes by a factor of 103-104, primarily due to low activation energies. A second Me group at the 2-position increased the rate by another power of 10. The addn. of one or more Me groups as substituents at the 4- and 5-position had a more complex influence on the rate of hydrolysis, most likely because of interaction of steric strain and polar effects. The polar factors involved were similar to those observed in acyclic acetals. The steric strain considerations which involved the partial 2,3-double bond after proton uptake at the 1-position also permitted distinguishing between cis- and trans-2,4-dimethyl-1,3-dioxolane, the cis form hydrolyzing about 4 times faster than the trans form.(i) Jacques, S. A.; Leriche, G.; Mosser, M.; Nothisen, M.; Muller, C. D.; Remy, J.-S.; Wagner, A. From solution to in-cell study of the chemical reactivity of acid sensitive functional groups: a rational approach towards improved cleavable linkers for biospecific endosomal release. Org. Biomol. Chem. 2016, 14, 4794– 4803, DOI: 10.1039/C6OB00846A[Crossref], [PubMed], [CAS], Google Scholar15ihttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XnsVaisL4%253D&md5=b22f2d7b9ab4902cac27f8bfc474aee1From solution to in-cell study of the chemical reactivity of acid sensitive functional groups: a rational approach towards improved cleavable linkers for biospecific endosomal releaseJacques, Sylvain A.; Leriche, Geoffray; Mosser, Michel; Nothisen, Marc; Muller, Christian D.; Remy, Jean-Serge; Wagner, AlainOrganic & Biomolecular Chemistry (2016), 14 (21), 4794-4803CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)PH-Sensitive linkers designed to undergo selective hydrolysis at acidic pH compared to physiol. pH can be used for the selective release of therapeutics at their site of action. In this paper, the hydrolytic cleavage of a wide variety of mol. structures that have been reported for their use in pH-sensitive delivery systems was examd. A wide variety of hydrolytic stability profiles were found among the panel of tested chem. functionalities. Even within a structural family, a slight modification of the substitution pattern has an unsuspected outcome on the hydrolysis stability. This work led us to establish a first classification of these groups based on their reactivities at pH 5.5 and their relative hydrolysis at pH 5.5 vs. pH 7.4. From this classification, four representative chem. functions were selected and studied in-vitro. The results revealed that only the most reactive functions underwent significant lysosomal cleavage, according to flow cytometry measurements. These last results question the acid-based mechanism of action of known drug release systems and advocate for the importance of an in-depth structure-reactivity study, using a tailored methodol., for the rational design and development of bio-responsive linkers.
- 16Blanco-Ania, D.; Rutjes, F. P. J. T. Carbonylonium ions: the onium ions of the carbonyl group. Beilstein J. Org. Chem. 2018, 14, 2568– 2571, DOI: 10.3762/bjoc.14.233[Crossref], [PubMed], [CAS], Google Scholar16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitVKit7%252FO&md5=58b4ec63a878f46fcdf0a1cb1430f301Carbonylonium ions: the onium ions of the carbonyl groupBlanco-Ania, Daniel; Rutjes, Floris P. J. T.Beilstein Journal of Organic Chemistry (2018), 14 (), 2568-2571CODEN: BJOCBH; ISSN:1860-5397. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)The nomenclature of cations R1C(=O+R3)R2 (R1, R2, R3 = H or organyl) has been examd. and shown to be in a state of immeasurable confusion: a pragmatic recommendation is made that the generic term "carbonylonium ions" should be adopted for these intermediates, which comprises the terms "aldehydium" (R1 = H, R2, R3 = H or organyl) and "ketonium ions" (R1, R2 = organyl, R3 = H or organyl) for the corresponding aldehyde- and ketone-based intermediates, resp.
- 17(a) Fife, T. H.; Hagopian, L. Steric effects in ketal hydrolysis. J. Org. Chem. 1966, 31, 1772– 1775, DOI: 10.1021/jo01344a024[ACS Full Text.], [CAS], Google Scholar17ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF28Xkt1Sjurs%253D&md5=02c3007410650211c380581d63381f60Steric effects in ketal hydrolysisFife, Thomas H.; Hagopian, LilyJournal of Organic Chemistry (1966), 31 (6), 1772-5CODEN: JOCEAH; ISSN:0022-3263.The rates of acid-catalyzed hydrolysis of diethyl ketal and 2,2-disubstituted 1,3-dioxolane derivs. of both aromatic and aliphatic ketones have been measured in 50% dioxane-H2O at 30°. The 1,3-dioxolane derivs. of BzMe and BzEt hydrolyze considerably slower than 2-phenyl-1,3-dioxolane, whereas the diethyl ketal derivs. of these ketones hydrolyze much faster than does BzH diethyl acetal, indicating the presence of a large steric retardation of the rate of hydrolysis of the 2-phenyl-2-alkyl-1,3-dioxolanes. The rates of hydrolysis of 2,2-dialkyl-1.3-dioxolanes appear to be subject to smaller steric effects. The observed retardations in rate are assocd. with less favorable ΔH* values. Values of ΔS* are nearly const. for all of the 2-phenyl-1,3-dioxolanes. A const. ΔS* difference of 8-10 e.u. appears to exist between 1,3-dioxolanes and the corresponding diethyl acetal or ketal regardless of substitution at the 2-position.(b) McClelland, R. A.; Watada, B.; Lew, C. S. Q. Reversibility of the ring-opening step in the acid hydrolysis of cyclic acetophenone acetals. J. Chem. Soc., Perkin Trans. 2 1993, 1723– 1727, DOI: 10.1039/p29930001723[Crossref], [CAS], Google Scholar.17bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXktlCmt7Y%253D&md5=37a6d2e3e80a6a8abf2fccea6d28c14aReversibility of the ring-opening step in the acid hydrolysis of cyclic acetophenone acetalsMcClelland, Robert A.; Watada, Brian; Lew, Calvin S. Q.Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999) (1993), (10), 1723-7CODEN: JCPKBH; ISSN:0300-9580.The acid-catalyzed hydrolysis of the vinyl ethers α-(3-hydroxyethoxy)styrene 1a or α-(3-hydroxypropoxy)styrene 1b yields a mixt. of acetophenone and a cyclic acetophenone acetal, 2-methyl-2-phenyl-1,3-dioxolane3a or 2-methyl-2-phenyl-1,3-dioxane 3b. The [acetophenone]:[3] ratios, detd. by HPLC and UV, are 15 from 1a and 10 from 1b. The acetals undergo further hydrolysis, but this is considerably slower than that of the vinyl ethers, and the above nos. represent products of kinetics control. These product ratios are equal to the rate const. ratios k2:k-1 for the partitioning of the oxocarbocations 1-(2-hydroxyethoxy)-1-phenylethyl 2a of 1-(3-hydroxypropoxy)-1-phenylethyl 2b between reaction with solvent water mols. and with the internal hydroxy group. These cations are also formed as intermediates in the hydrolysis of the cyclic acetals 3. That k2 is an order of magnitude greater than k-1 signifies that the rate-limiting step in this hydrolysis is the ring-opening forming the oxocarbocation, and that there is little reversibility in aq. solns. The hydrolysis reactions of these cyclic acetals are considerably slower than that of an acyclic analog, the di-Me acetal of acetophenone, by factors of 1.0 × 103 for 3a and 1.8 × 102 for 3b. This study demonstrates that these rate retardations cannot be accounted for by reversibility of the ring-opening step. The presence of the ring results in an inherent decrease in the rate const. for the H+-catalyzed formation of the oxocarbocation.(c) Knowles, J. P.; Whiting, A. The effects of ring size and substituents on the rates of acid-catalysed hydrolysis of five- and six-membered ring cyclic ketone acetals. Eur. Eur. J. Org. Chem. 2007, 2007, 3365– 3368, DOI: 10.1002/ejoc.200700244 .(d) Liu, B.; Thayumanavan, S. Substituent effects on the pH sensitivity of acetals and ketals and their correlation with encapsulation stability in polymeric nanogels. J. Am. Chem. Soc. 2017, 139, 2306– 2317, DOI: 10.1021/jacs.6b11181[ACS Full Text], [CAS], Google Scholar17dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsVagt78%253D&md5=b265a1435bcc42b4fce000034d13d279Substituent Effects on the pH Sensitivity of Acetals and Ketals and Their Correlation with Encapsulation Stability in Polymeric NanogelsLiu, Bin; Thayumanavan, S.Journal of the American Chemical Society (2017), 139 (6), 2306-2317CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)The effect of structural variations in acetal- and ketal-based linkers upon their degrdn. kinetics is studied through the design, synthesis, and study of six series of mols., comprising a total of 18 different mols. Through this systematic study, the structural fine-tuning of the linkers allows access to variations in kinetics of degrdn. of >6 orders of magnitude. Hammett correlations show that the ρ value for the hydrolysis of benzylidene acetals is ∼-4.06, which is comparable to an SN1-like process. There is a strong, developing pos. charge at the benzylic position in the transition state during the degrdn. of acetals. This pos. charged transition state is consistent with the relative degrdn. rates of acetals vs. ketals (correlated to stabilities of 1°, 2°, and 3° carboxonium ion type intermediates) and the obsd. effect of proximal electron-withdrawing groups upon the degrdn. rates. Following this, the authors studied whether the degrdn. kinetics study correlates with pH-sensitive variations in the host-guest characteristics of polymeric nanogels that contains these acetal or ketal moieties as crosslinking functionalities. Indeed, the trends obsd. in the small mol. degrdn. have clear correlations with the encapsulation stability of guest mols. within these polymeric nanogels. The implications of this fundamental study extend to a broad range of applications, well beyond the polymeric nanogel examples studied here.
- 18Miller, S. R.; Krasutsky, S.; Kiprof, P. Stability of carboxonium ions. J. Mol. Struct.: THEOCHEM 2004, 674, 43– 47, DOI: 10.1016/j.theochem.2003.12.044[Crossref], [CAS], Google Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXjsVCkt7s%253D&md5=4377259364607f8273f0f65712a0d3edStability of carboxonium ionsMiller, Stephen R.; Krasutsky, Sergiy; Kiprof, PaulJournal of Molecular Structure: THEOCHEM (2004), 674 (1-3), 43-47CODEN: THEODJ; ISSN:0166-1280. (Elsevier Science B.V.)Carboxonium ions were studied through anal. of the bonding situation in terms of natural bond order, natural resonance structure contributors and charges. The stabilizing effect of oxygen was also elucidated through hydride exchange reactions and study of the π interactions of the cationic carbon with oxygen substituents.
- 19Carey, F. A.; Sundberg, R. J. Reaction of Carbonyl Compounds. Advanced Organic Chemistry 1977, 325– 360, DOI: 10.1007/978-1-4613-9792-2_8
- 20(a) Guthrie, J. P. Carbonyl addition reactions. Factors affecting the hydrate-hemiacetal and hemiacetal-acetal equilibrium constants. Can. J. Chem. 1975, 53, 898– 906, DOI: 10.1139/v75-125[Crossref], [CAS], Google Scholar.20ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE2MXlsVKru70%253D&md5=230f58d8019ca38412534a1ed11781dfCarbonyl addition reactions. Factors affecting the hydrate-hemiacetal and hemiacetal-acetal equilibrium constantsGuthrie, J. PeterCanadian Journal of Chemistry (1975), 53 (6), 898-905CODEN: CJCHAG; ISSN:0008-4042.Equil. consts. for hydrate-hemiacetal interconversion in aq. soln. at 25° have been measured for four fluorinated carbonyl compds.: compd., alc., K4 (M-1): CF3CHO, EtOH, 2.3; CF3COMe, MeOH, 1.0; CF3COPh, MeOH, 3.5; CF3COCF3, MeOH, 0.14. These values, combined with values from the literature, permitted an examn. of substituent effects upon the equil. const. for C-OH + ROH ↹ C-OR + H2O. The free energy change for this process, corrected for symmetry and steric effects, followed the equation ΔG4'' = -0.54 + 0.63 Σσ*. Electronic effects upon this equil. were generally small and in fact were often smaller than steric effects. This anal. permitted calcn. of free energies of formation of C-OH compds. from the free energies of formation of the analogous C-OR compds.(b) Greenzaid, P.; Luz, Z.; Samuel, D. A nuclear magnetic resonance study of the reversible hydration of aliphatic aldehydes and ketones. I. Oxygen-17 and proton spectra and equilibrium constants. J. Am. Chem. Soc. 1967, 89, 749– 756, DOI: 10.1021/ja00980a004[ACS Full Text], [CAS], Google Scholar20bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF2sXmsV2juw%253D%253D&md5=0cbf3d1e2957789d34b12aaea9da3a4eA nuclear magnetic resonance study of the reversible hydration of aliphatic aldehydes and ketones. I. Oxygen-17 and proton spectra and equilibrium constantsGreenzaid, Peniel; Luz, Zeev; Samuel, DavidJournal of the American Chemical Society (1967), 89 (4), 749-56CODEN: JACSAT; ISSN:0002-7863.17O N.M.R. spectra of aq. solns. of a no. of aliphatic carbonyl compds. enriched in 17O are reported. The resonances of the unhydrated carbonyl species and of the hydrated gem-diol species fall in two different regions. The carbonyl O resonance falls in the range -520 to -560 ppm. (relative to H217O), and that of the gem-diol falls close to the water line, often being concealed by it. P.M.R. spectra were also studied and used to det. equil. consts., Kd, for the hydration-dehydration reaction of the carbonyl group. A good correlation between Kd values, which span a range of seven orders of magnitude, and Σσ* is obtained provided account is taken of the no. of aldehydic protons in the mol. The following free-energy relationship between Kd and Σσ* is proposed, -log Kd = ρ* Σσ* + BΔ + C, where ρ*, B, and C are consts., and Δ is the no. of aldehydic hydrogens in the mol. A best-fit analysis gave ρ* = 1.70 ± 0.07, B = 2.03 ± 0.10, and C = -2.81 ± 0.13. These results are discussed in terms of adjacent bond interaction. 28 references.
- 21Butler, T. C. The introduction of chloral hydrate into medical practice. Bull. Hist. Med. 1970, 44, 168– 172[PubMed], [CAS], Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaE3c3ktVShsw%253D%253D&md5=cb658517712333264738af5be072a435The introduction of chloral hydrate into medical practiceButler T CBulletin of the history of medicine (1970), 44 (2), 168-72 ISSN:0007-5140.There is no expanded citation for this reference.
- 22(a) West, R. Siegfried Ruhemann and the discovery of ninhydrin. J. Chem. Educ. 1965, 42, 386– 388, DOI: 10.1021/ed042p386[ACS Full Text.], [CAS], Google Scholar22ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF2MXkt1Onu7s%253D&md5=cb1388b8bc927de60fc642c5e49a152aSiegfried Ruhemann and the discovery of ninhydrinWest, RobertJournal of Chemical Education (1965), 42 (7), 386-7CODEN: JCEDA8; ISSN:0021-9584.A biographical review.(b) Odén, S.; von Hofsten, B. Detection of fingerprints by the ninhydrin reaction. Nature 1954, 173, 449– 450, DOI: 10.1038/173449a0[Crossref], [PubMed], [CAS], Google Scholar22bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaG2cXjvVOrtw%253D%253D&md5=50d1fa5ba15d6e398cdc5d8134c8c41fDetection of fingerprints by the ninhydrin reactionOden, Svante; v. Hofsten, BengtNature (London, United Kingdom) (1954), 173 (), 449-50CODEN: NATUAS; ISSN:0028-0836.A spontaneous fingerprint contains 98.5-99.5% H2O, the rest being org. and inorg. compds. Normally, the H2O will evap. leaving the rest as a fingerprint pattern contg. fats, salts, amino acids, etc. The amino acids give the well known color reaction with ninhydrin. This offers a good method for detecting fingerprints on paper and similar materials. Fingerprints are developed by spraying the paper with a 0.2% soln. of ninhydrin in acetone, followed by heating in an oven at 80° for a few min. This initiates the process, and the pink color becomes more intense with time and new marks appear as the developing process matures. Details have a max. distinctness a day or two after the ninhydrin treatment.
- 23Simmons, H. E.; Wiley, D. W. Fluoroketones. J. Am. Chem. Soc. 1960, 82, 2288– 2296, DOI: 10.1021/ja01494a047[ACS Full Text], [CAS], Google Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF3cXhtFSmtLo%253D&md5=c61f15a230dee2aa651333cd718be719Fluoro ketones. ISimmons, Howard E., Jr.; Wiley, Douglas W.Journal of the American Chemical Society (1960), 82 (), 2288-96CODEN: JACSAT; ISSN:0002-7863.(CClF2)2CO (I) (CCl2F)2CO (II), (CF3)2CO (III), and CF3Ac (IV) were converted by a novel base-catalyzed ketalization to ketals of unusual thermal and chem. stability; this synthesis was also extended to dioxolanes, dioxanes, oxazolidines, oxathiolanes, and their carbonyl-contg. analogs. The fluoro ketones react with CH2N2 to give high yields of stable epoxides and condense readily with active methylene compds. and metallic acetylides. I and NH3 gave 100% (CClF2)2C(OH)NH2, m. 67-8°. I (25.0 g.) treated slowly with stirring with 5.8 g. abs. EtOH followed by 15.9 g. Me2SO4, and finally by 15 g. K2CO3 in small portions during 1 hr. while small amts. of pentane were added to keep the mixt. fluid, the mixt. poured after 4 hrs. into 100 cc. cold H2O, and the product isolated with pentane gave 15.1 g. (CClF2)2C(OMe)OEt (V), b51 79-80°, n25D 1.3857, also obtained in 25% yield by alkylating (CClF2)2C(OH)OEt (VI) with MeI and Ag2O. Similarly were prepd. the following (CClF2)C(OMe)OR (R, b.p./mm., n25D, and % yield given): Me, 147-8°/760, 1.3829, 47; EtMeCH, 71.5°/15, 1.3965, 40; C3F7CH2, 73°/25, 1.3406, 61; H(CF2)10CH2, 150-4°/12, 1.3395, 48. (C3F7)2C(OMe)2 b. 72-3°/48, 1.3105, 92. I (50.0 g.) and 20.2 g. Cl(CH2)2OH (VII) stirred 15 min., dild. with 50 cc. pentane, treated with 35 g. K2CO3 in portions during 1 hr., stirred 2 hrs., and poured into H2O, the aq. phase extd. with pentane, and the combined org. phase and ext. fractionated gave 51.3 g. 2,2-bis(chlorodifluoromethyl)-1,3-dioxolane (VIII), b. 171-2°, n25D 1.3896, also obtained in 30% yield by adding an equimolar mixt. of I and VII to 15% aq. KOH and extg. with pentane. Similarly were prepd. the following compds. (b.p./mm., n25D, and % yield given): 2,2-bis(trifluoromethyl)-1,3-dioxolane, 99-100°/760, 1.3088, 16 (from III); 2,2-bis(dichlorofluoromethyl)-1,3-dioxolane, 65-6°/l, 1.4680, 42 (from II); 2-trifluoromethyl-1,3-dioxolane, 92°/760, 1.3353, 11; 2,2-bis(chlorodifluoromethyl)4-chloromethyl-1,3-dioxolane, 74°/6, 1.4171, 88, 2,2-bis(chlorodifluoromethyl)-1,3-dioxane, 112-13°/50, 1.4109, 37. (CCl3)2CO (20.0 g.), 9.2 g. VII, 15.6 g. K2CO3, and 60 cc. pentane stirred at room temp. overnight, poured into 100 cc. H2O, and extd. with pentane, and the ext. worked up gave 15.1 g. CCl3CO2(CH2)2Cl, b0.2 57°, n25D 1.4782. IV (25.0 g.) and 18.0 g. VII treated with 30.8 g. K2CO3 in portions during 1 hr. with stirring and cooling, stirred 4 hrs. at room temp., and poured into 150 cc. H2O, and the product isolated with pentane gave 28 g. crude product which fractionated yielded 13 g. 5,7-bis(trifluoromethyl)-5-hydroxy-7-methyl-1,4-dioxacycloheptane (IX), b11 69-70°, n25D 1.3675, and 12 g. 2,4-dihydroxy-6-methyl-2,4,6-tris(trifluoromethyl)pyran (X), b10 77-8°, m. 107-8° (pentane). IX and X form salts with LiH in Et2O. I (120 g.) treated during 10 min. with stirring and cooling with 33.6 g. CH.tbd.CCH2OH, b. 113-15°, the mixt. treated with 2 g. yellow HgO in 4 portions at 5-min. intervals, kept 4 hrs. at 35°, and fractionated gave 129 g. 4-methylene deriv. of VIII, b13 51-3°, n25D 1.3982, d2525 1.514. CH.tbd.C(CH2)2OH yielded similarly 74% 2,2-bis(chlorodifluoromethyl)-4-methylene-1,3-dioxane, b22 86-8°, n25D 1.4192, d25 1.505. VIII (24.3 g.) in 200 cc. CCl4 treated with stirring and irradiation with a sunlamp during 3 hrs. with 7.1 g. Cl and fractionated gave 18.0 g. 4-Cl deriv. of VIII, b750 179-80°, n25D 1.4050, 1.4093, d25 1.657, 1.669. Similar runs with more Cl and at higher temps. gave the following derivs. of VIII (substituents, b.p./750 mm., n25D, and d25 given): 4,5(or 4,4)-di-Cl, 182-4°, 1.4159, 1.692; 4,4,5-tri-Cl, 199-200°, 1.4319, 1.755; 4,4,5,5-tetra-Cl, 218-19°, 1.4466, 1.811. I (25.0 g. in 50 cc. dry Et2O treated dropwise with stirring with 10.7 g. piperidine in 50 cc. dry Et2O at -20°, the mixt. treated successively with 15.9 g. Me2SO4 and 15 g. K2CO3, warmed to room temp., stirred overnight, dild. with H2O, and extd. with Et2O, and the ext. worked up gave 2.5 g. 1-(chlorodifluoroacetyl)piperidine, b0.55 63°, n25D 1.4512, also obtained in 62% yield at 0°. Br(CH2)2NH2 (41.0 g.) in 75 cc. HCONMe2 treated with cooling with 79.6 g. I, the mixt. treated during 1 hr. with 55.4 g. K2CO3 in small portions, stirred 2 hrs., poured into 400 cc. H2O, and extd. with Et2O, and the ext. worked up gave 40.8 g. 2,2-bis(chlorodifluoromethyl)-1,3-oxazolidine (X), b177 138-9°, n25D 1.4122, d25 1.596; X was sol. in concd. H2SO4; it formed with dry HCl a salt which reverted to X by shaking with H2O. I (80 g.) added slowly with cooling and stirring to 19.3 g. Cl(CH2)2SH in 50 cc. Et2O, the mixt. treated with a trace NaOMe, stirred 1 hr., treated with 27.6 g. K2CO3, poured into H2O, and extd. with Et2O, and the ext. worked up gave 17.3 g. 2,2-bis(chlorodifluoromethyl)-1,3-oxathiolane (XI), b9 76°, n25D 1.4414. HOCH2CO2H (30.4 g.) in 50 cc. HCONMe2 treated with 89.0 g. I with stirring and cooling, the mixt. treated with 1 g. NaOAc, kept 3 days, and poured into 1 l. H2O, and the product isolated with CH2Cl2 yielded 52.7 g. 4-oxo deriv. (XII) of VIII, b. 159-61°, n25D 1.3870. Me2C(OH)CO2Et (25.4 g.) added with cooling and stirring to 39.8 g. I in 75 cc. Et2O, treated with 2 g. NaOAc, stirred 48 hrs., filtered, and fractionated gave 24.1 g. VI, b. 108°, n25D 1.3837, and 18.2 g. 5,5-di-Me deriv. of XII, b. 169°, n25D 1.3925. In the same manner as XII was prepd. the 5-oxo deriv. of XI, b50 120°, n25D 1.4388, d25 1.706, in 49% yield. DL-Alanine (13.4 g.) and 60.0 g. I treated with 50 cc. HCONMe2, heated 3 hrs. at 60°, dissolved in 85 cc. CH2Cl2, and poured into 850 cc. H2O, and the product isolated with CH2Cl2 gave 33.2 g. 5-oxo deriv. of X, b16 104°, n25D 1.4099, d25 1.065. H2NCH2CO2H and I gave similarly a crude product which decompd. extensively during an attempted distn. with the formation of HF and CO2. I (90.0 g.) added dropwise during 2 hrs. at 0° to 0.45 mole CH2N2 in 800 cc. Et2O and fractionated yielded 74.0 g. 2,2-bis(chlorodifluoromethyl)oxirane (XIII), b. 106-7°, n25D 1.3670. II and CH2N2 gave similarly 2,2-bis(dichlorofluoromethyl)oxirane, b30 90-1°, n25D 1.4522. (C3F7)2CO and CH2N2 yielded 2,2-bis(heptafluoropropyl)oxirane, b. 120-1°, n25D 1.2932. XIII (10.0 g.) and 9 cc. 46% aq. HBr stirred over a weekend, refluxed several hrs., neutralized with 10% aq. NaHCO3, and extd. with Et2O, and the ext. worked up gave 3.4 g. unchanged XIII and 4.7 g. (CClF2)2C(OH)CH2Br, b. 167-9°, n25D 1.4303. I (25.0 g.) and 14.2 g. NCCH2CO2Et kept 15 min., treated with 20.0 g. AcCl and then during 45 min. with stirring with 10 cc. C5H5N, stirred 0.5 hr., warmed 15 min. on the steam bath, and poured into 125 cc. iced H2O, and the product isolated with pentane gave 20.6 g. (CClF2)2C:C(CN)CO2Et, b0.2 47-8°, n25D 1.4182. Na (28.8 g.) in 300 cc. dry NH3 treated with C2H2, the NH3 displaced with 300 cc. dry Et2O, the mixt. treated dropwise with stirring during 2 hrs. with 200 g. I in 100 cc. dry Et2O, stirred overnight, and dild. with 200 cc. H2O, the aq. phase extd. with Et2O, and the combined Et2O solns. worked up yielded 180 g. (CClF2)2C(OH)C.tbd.CH (XIV), b16 41-2°, n25D 1.3940, pKA 8.92, 8.95 (50% aq. EtOH). III and Na2C2 yielded similarly 16% (CF3)2C(OH)C.tbd.CH (XV), b. 87-8°, n25D 1.3125. EtBr (82.0 g.), 20.2 g. Mg, and 240 cc. dry Et2O treated with stirring with C2H2, the mixt. treated dropwise during 1 hr. with stirring and cooling with 100 g. I in 100 cc. dry Et2O, stirred 24 hrs. at room temp., and treated with cooling with 200 cc. 5N HCl, and the product isolated with Et2O gave 20.5 g. XIV, b18 40-1°, n25D 1.3862; the pot residue recrystd. from Et2O yielded 56.4 g. [.tbd.CC(CClF2)2OH]2, (XVI), m. 51-2°, pKA1 7.35, 7.45, pKA2 10.03, 10.05 (50% aq. EtOH). XIV (15.0 g.) and 7.9 g. AcCl treated at 0° dropwise with stirring with 6 cc. C5H5N, stirred 2 hrs. at 0°, and dild. with 100 cc. iced H2O, and the product isolated with pentane yielded 16.5 g. acetate of XIV, b14 66-7°, n25D 1.4031. XIV (10.00 g.) in 10 cc. dry C6H6 added dropwise with stirring to 1.06 g. NaH in 60 cc. dry C6H6, stirred 0.5 hr., refluxed 2 days with 8.48 g. p-MeC6H4SO2Cl, washed with 5% aq. NaHCO3 and H2O, dried, and distd., and the distillate (11.2 g.) sublimed gave the 3-(p-toluenesulfonate) of XIV, m. 43-4°. Similarly were prepd. the 3-(p-toluenesulfonate) of XV, m. 36-7° (pentane), 78%, and the 1,4-bis(p-toluenesulfonate) of XVI, m. 189-90° (Me2CO), 75%. I (4.7 g.), 5.0 g. XVI, 3.0 g. Me2SO4, and 1.4 g. K2CO3 stirred 20 hrs. at room temp., the mixt. poured into 100 cc. H2O, and the product isolated with pentane gave 2.5 g. di-Me ether of XVI, b0.2 67°, n25D 1.4061. XIV (22.5 g.), 25.0 g. CuCl, 40.0 g. NH4Cl, and 100 cc. H2O shaken 1 hr. and extd. with Et2O, and the ext. worked up gave 11.5 g. [C.tbd.CC(OH)(CClF2)2]2, m. 79-80° (sublimed). XIV (50.0 g.) and 52.0 g. PCl5 heated 1 hr. on the steam bath, poured onto 400-500 g. crushed ice, and shaken 2 min., and the product isolated with 200 cc. pentane gave 4.3 g. unchanged XIV and 26.6 g. CF2:C(CClF2)CCl:CHCl, b38 43°, n25D 1.4152. XVI (10.0 g.) and 9.8 g. PCl5 refluxed 0.5 hr., and poured onto 200-300 g. crushed ice, the mixt. shaken 2 min., the org. phase extd. with hexane, and the ext. worked up yielded 6.0 g. (CClF2)2CClC≡CC(OH)(CClF2)2, b1.7 69-70°, n25D 1.4300.
- 24Bagnall, R. D.; Bell, W.; Pearson, K. New inhalation anaesthetics: I. Fluorinated 1,3-dioxolane derivatives. J. Fluorine Chem. 1977, 9, 359– 375, DOI: 10.1016/S0022-1139(00)82169-7[Crossref], [CAS], Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE2sXls1OqsL0%253D&md5=c72f090f8367e29086f24ee79e0d71afNew inhalation anesthetics. I. Fluorinated 1,3-dioxolane derivativesBagnall, R. D.; Bell, W.; Pearson, K.Journal of Fluorine Chemistry (1977), 9 (5), 359-75CODEN: JFLCAR; ISSN:0022-1139.Thirty-five fluorochlorodioxolanes I (R = R1 = H, Cl, F; R = F, R1 = Cl, H; R2, R3, R4, R5 = H, F, Cl), prepd. by chlorination, fluorination and redn. of polyfluoroalkyl-1,3-dioxolanes, were screened for their anesthetic activity. Only 2-(trifluoromethyl)-1,3-dioxolane showed good anesthesia without side effects, but is probably flammable at clinical concns.
- 25Brown, H. C.; Okamoto, Y. Substituent constants for aromatic substitution. J. Am. Chem. Soc. 1957, 79, 1913– 1917, DOI: 10.1021/ja01565a039[ACS Full Text], [CAS], Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaG2sXms1CmsQ%253D%253D&md5=44b78022d40102be542b5be2f9cd3a6eSubstituent constants for aromatic substitutionBrown, Herbert C.; Okamoto, Y.Journal of the American Chemical Society (1957), 79 (), 1913-17CODEN: JACSAT; ISSN:0002-7863.A plot of the logarithms of the rate consts. for the solvolysis of the m- and p-substituted phenyldimethylcarbinyl chlorides against the Hammett σ-consts. showed an excellent correlation in the case of the m-derivs. but serious deviations for the p-substituents. The deviations are in the direction to be anticipated for important resonance interactions between the p-substituent and the electron-deficient center of the incipient carbonium ion in the transition state. The ρ-value of -4.620 was established for the reactions of the m-derivs. A new set of σ+-consts. for the p-substituents was calcd. from this ρ-value and the observed solvolysis rates (substituent and σp+-value given): MeO, -0.764; Me, -0.306; Et, -0.291; iso-Pr, -0.276; Me3C, -0.250; F, -0.0714; Cl, 0.112, Br, 0.148; iodine, 0.132; NO2, 0.777; 3,4-(CH2)4, -0.132. Similarly were established the following new σm+ values for the following substituents: MeO, 0.0465; Et, -0.0625; iso-Pr, -0.0589; Me3C, -0.0581; NO2, 0.662. The new σp+-values give good agreement with the available data on the rates of the nitration of monosubstituted aromatics, the halogenation of aromatics, the brominolysis of arylboronic acids, and the protonolysis of aryltrimethylsilanes.
- 26Lowe, D. In The Pipeline. https://blogs.sciencemag.org/pipeline/archives/2015/11/05/another-funny-looking-structure-comes-through (accessed March 12, 2021).
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- 28Maryanoff, B. E.; Costanzo, M. J.; Nortey, S. O.; Greco, M. N.; Shank, R. P.; Schupsky, J. J.; Ortegon, M. P.; Vaught, J. L. Structure-activity studies on anticonvulsant sugar sulfamates related to topiramate. Enhanced potency with cyclic sulfate derivatives. J. Med. Chem. 1998, 41, 1315– 1343, DOI: 10.1021/jm970790w[ACS Full Text], [CAS], Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXitFGju7o%253D&md5=d79f854b98ec4de7b065af4e42d3be59Structure-Activity Studies on Anticonvulsant Sugar Sulfamates Related to Topiramate. Enhanced Potency with Cyclic Sulfate DerivativesMaryanoff, Bruce E.; Costanzo, Michael J.; Nortey, Samuel O.; Greco, Michael N.; Shank, Richard P.; Schupsky, James J.; Ortegon, Marta P.; Vaught, Jeffry L.Journal of Medicinal Chemistry (1998), 41 (8), 1315-1343CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The authors have explored the structure-activity relationship (SAR) surrounding the clin. efficacious antiepileptic drug topiramate (I), a unique sugar sulfamate anticonvulsant that was discovered in our labs. Systematic structural modification of the parent compd. was directed to identifying potent anticonvulsants with a long duration of action and a favorable neurotoxicity index. In this context, we have probed the pharmacol. importance of several mol. features: (1) the sulfamate group, (2) the linker between the sulfamate group and the pyran ring, (3) the substituents on the 2,3- and 4,5-fused 1,3-dioxolane rings, (4) the constitution of the 4,5-fused 1,3-dioxolane ring, (5) the ring oxygen atoms, and (6) the abs. stereochem. The authors established the C1 configuration as R for the predominant alc. diastereomer from the highly selective addn. of methylmagnesium bromide to aldehyde by single-crystal X-ray anal. of the major diastereomer of sulfamate. Details for the stereoselective syntheses of the hydrindane carbocyclic analogs are presented. The authors also report the synthesis of cyclic imidosulfites and imidosulfate, which are rare examples in the class of such five-membered-ring sulfur species. Imidosulfite required the prepn. and use of the novel sulfur dichloride reagent, BocN:SCl2. Our SAR investigation led to the impressive 4,5-cyclic sulfate analog (II) (RWJ-37947), which exhibits potent anticonvulsant activity in the maximal electroshock seizure (MES) test (ca. 8 times greater than I in mice at 4 h, ED50 = 6.3 mg/kg; ca. 15 times greater than I in rats at 8 h, ED50 = 1.0 mg/kg) with a long duration of action (>24 h in mice and rats, po) and very low neurotoxicity (TD50 value of >1000 mg/kg at 2 h, po in mice). Cyclic sulfate II, like topiramate and phenytoin, did not interfere with seizures induced by pentylenetetrazole, bicucculine, picrotoxin, and strychnine; also, II was not active in diverse in vitro receptor binding and uptake assays. However, II turned out to be a potent inhibitor of carbonic anhydrase from different rat tissue sources (e.g., IC50 of 84 nM for the blood enzyme and 21 nM for the brain enzyme). An examn. of several analogs of II indicated that potent anticonvulsant activity is assocd. with relatively small alkyl substituents on nitrogen (Me/H, Me/Me, Et/H, allyl/H, c-Pr/H, c-Bu/H,) and with limited changes in the cyclic sulfate group, such as 4,5-cyclic sulfite. The potent anticonvulsants had greatly diminished carbonic anhydrase inhibitory activity; thus, inhibition of this enzyme may not be a significant factor in the anticonvulsant activity. The α-L-sorbopyranoses, which mainly possess a skew conformation (ref 29), were nearly twice as potent as I. The L-fructose ent-I and ent-II, synthesized from L-sorbose, were found to have moderate anticonvulsant activity, with eudysmic ratios (MES ED50 in mice at 4 h, po) of I:ent-I = 1.5 and II:ent-II = 8.0. Log P values for I and II were detd. exptl. to be 0.53 and 0.42, resp., which are less than the optimal 2.0 for CNS active agents. However, analogs with more favorable calcd. log P (clogP) values, in conjunction with just minor steric perturbation according to the developed SAR profile did not display improved potency. Although the measured log P value for di-Et is 1.52, this did not translate into enhanced potency relative to I. The 400-MHz 1H NMR studies of I and II indicated that the skew 3S0 conformer predominates at ambient temp. in nonaq. and aq. media; hydrindane (III) strongly populates a skew 3S0 conformer in benzene. X-ray crystal structures for I, II, and III depict the skew 3S0 conformer in the solid state. Soln. IR studies showed an absence of intramol. hydrogen bonding, in contrast to what has been obsd. for alc. 4 (ref 73).
- 29Rankovic, Z. CNS drug design: balancing physicochemical properties for optimal brain exposure. J. Med. Chem. 2015, 58, 2584– 2608, DOI: 10.1021/jm501535r[ACS Full Text], [CAS], Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitVyhsrrP&md5=f01e3f2dc4e2eff7b0618124277a5cf8CNS Drug Design: Balancing Physicochemical Properties for Optimal Brain ExposureRankovic, ZoranJournal of Medicinal Chemistry (2015), 58 (6), 2584-2608CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. The human brain is a uniquely complex organ, which has evolved a sophisticated protection system to prevent injury from external insults and toxins. Designing mols. that can overcome this protection system and achieve optimal concn. at the desired therapeutic target in the brain is a specific and major challenge for medicinal chemists working in CNS drug discovery. Analogous to the now widely accepted rule of 5 in the design of oral drugs, the physicochem. properties required for optimal brain exposure have been extensively studied in an attempt to similarly define the attributes of successful CNS drugs and drug candidates. This body of work is systematically reviewed here, with a particular emphasis on the interplay between the most crit. physicochem. and pharmacokinetic parameters of CNS drugs as well as their impact on medicinal chem. strategies toward mols. with optimal brain exposure. A summary of modern CNS pharmacokinetic concepts and methods is also provided.
- 30Brand, S.; Norcross, N. R.; Thompson, S.; Harrison, J. R.; Smith, V. C.; Robinson, D. A.; Torrie, L. S.; McElroy, S. P.; Hallyburton, I.; Norval, S.; Scullion, P.; Stojanovski, L.; Simeons, F. R.; Aalten, D. V.; Frearson, J. A.; Brenk, R.; Fairlamb, A. H.; Ferguson, M. A.; Wyatt, P. G.; Gilbert, I. H.; Read, K. D. Lead optimization of a pyrazole sulfonamide series of Trypanosoma brucei N-!myristoyltransferase inhibitors: identification and evaluation of CNS penetrant compounds as potential treatments for stage 2 human African trypanosomiasis. J. Med. Chem. 2014, 57, 9855– 9869, DOI: 10.1021/jm500809c[ACS Full Text], [CAS], Google Scholar30https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvFKqu7rP&md5=6d6f5e8618aa3b7017b789f89d9540a5Lead Optimization of a Pyrazole Sulfonamide Series of Trypanosoma brucei N-Myristoyltransferase Inhibitors: Identification and Evaluation of CNS Penetrant Compounds as Potential Treatments for Stage 2 Human African TrypanosomiasisBrand, Stephen; Norcross, Neil R.; Thompson, Stephen; Harrison, Justin R.; Smith, Victoria C.; Robinson, David A.; Torrie, Leah S.; McElroy, Stuart P.; Hallyburton, Irene; Norval, Suzanne; Scullion, Paul; Stojanovski, Laste; Simeons, Frederick R. C.; van Aalten, Daan; Frearson, Julie A.; Brenk, Ruth; Fairlamb, Alan H.; Ferguson, Michael A. J.; Wyatt, Paul G.; Gilbert, Ian H.; Read, Kevin D.Journal of Medicinal Chemistry (2014), 57 (23), 9855-9869CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Trypanosoma brucei N-myristoyltransferase (TbNMT) is an attractive therapeutic target for the treatment of human African trypanosomiasis (HAT). From previous studies, we identified pyrazole sulfonamide, DDD85646 (1), a potent inhibitor of TbNMT. Although this compd. represents an excellent lead, poor central nervous system (CNS) exposure restricts its use to the hemolymphatic form (stage 1) of the disease. With a clear clin. need for new drug treatments for HAT that address both the hemolymphatic and CNS stages of the disease, a chem. campaign was initiated to address the shortfalls of this series. This paper describes modifications to the pyrazole sulfonamides which markedly improved blood-brain barrier permeability, achieved by reducing polar surface area and capping the sulfonamide. Moreover, replacing the core arom. with a flexible linker significantly improved selectivity. This led to the discovery of DDD100097 (40) which demonstrated partial efficacy in a stage 2 (CNS) mouse model of HAT.
- 31Christensen, J.; Højskov, C. S.; Dam, M.; Poulsen, J. H. Plasma concentration of topiramate correlates with cerebrospinal fluid concentration. Ther. Drug Monit. 2001, 23, 529– 535, DOI: 10.1097/00007691-200110000-00006[Crossref], [PubMed], [CAS], Google Scholar31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXnvVygt7k%253D&md5=528ff03f181f2edcfb4b2b3c9138ffa1Plasma concentration of topiramate correlates with cerebrospinal fluid concentrationChristensen, Jakob; Hojskov, Carsten S.; Dam, Mogens; Poulsen, Jorgen H.Therapeutic Drug Monitoring (2001), 23 (5), 529-535CODEN: TDMODV; ISSN:0163-4356. (Lippincott Williams & Wilkins)The authors examd. the ratio between the plasma and the cerebrospinal fluid (CSF) concn. of topiramate in 14 adults with epilepsy. Simultaneous trough samples of venous blood and CSF were collected and analyzed as total and unbound concns. Concomitant levels were also analyzed of Lamotrigine (n = 5) and the relevant oxcarbazepine metabolite, 10-hydroxycarbazepine (n = 3). There was a close correlation between the plasma and the CSF concn. for both the total and unbound concn. of topiramate. The median CSF/plasma ratio of total topiramate was 0.85. The free topiramate concn. in plasma was not different from the free topiramate concn. in CSF. The CSF/plasma ratios showed little variation and were independent of the plasma level for both the total and the unbound levels. The unbound fraction of topiramate was 84% in plasma and 97% in CSF. The CSF concns. of Lamotrigine and 10-hydroxycarbazepine were 50% and 61% of the plasma concns., resp. For topiramate, there is a close correlation between the plasma concn. and the CSF concn. There does not seem to be a saturable carrier mechanism restricting topiramate transport across the blood-brain barrier. The concn. of topiramate in CSF is equal to the unbound proportion of topiramate in plasma, implying that the delivery of topiramate to the brain occurs via transfer from the unbound plasma pool. Plasma is thus a relevant matrix for therapeutic drug monitoring of topiramate.
- 32Caldwell, G. W.; Wu, W. N.; Masucci, J. A.; McKown, L. A.; Gauthier, D.; Jones, W. J.; Leo, G. C.; Maryanoff, B. E. Metabolism and excretion of the antiepileptic/antimigraine drug, topiramate in animals and humans. Eur. J. Drug Metab. Pharmacokinet. 2005, 30, 151– 164, DOI: 10.1007/BF03190614[Crossref], [PubMed], [CAS], Google Scholar32https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtFCgtLrN&md5=03b77332c0c89dc042dc73672644af70Metabolism and excretion of the antiepileptic/antimigraine drug, topiramate in animals and humansCaldwell, Gary W.; Wu, W. N.; Masucci, J. A.; McKown, L. A.; Gauthier, D.; Jones, W. J.; Leo, G. C.; Maryanoff, B. E.European Journal of Drug Metabolism and Pharmacokinetics (2005), 30 (3), 151-164CODEN: EJDPD2; ISSN:0378-7966. (Medecine et Hygiene)The metab. and excretion of 2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose sulfamate (TOPAMAX, topiramate, TPM) have been investigated in animals and humans. Radiolabeled [14C]TPM was orally administered to mice, rats, rabbits, dogs and humans. Plasma, urine and fecal samples were collected and analyzed. TPM and a total of 12 metabolites were isolated and identified in these samples. Metabolites were formed by hydroxylation at the 7- or 8-Me of an isopropylidene of TPM followed by rearrangement, hydroxylation at the 10-Me of the other isopropylidene, hydrolysis at the 2,3-O-isopropylidene, hydrolysis at the 4,5-O-isopropylidene, cleavage at the sulfamate group, glucuronide conjugation and sulfate conjugation. A large percentage of unchanged TPM was recovered in animal and human urine. The most dominant metabolite of TPM in mice, male rats, rabbits and dogs appeared to be formed by the hydrolysis of the 2,3-O-isopropylidene group.
- 33Patsalos, P. N. The mechanism of action of topiramate. Rev. Contemp. Pharmacother. 1999, 10, 147– 153[CAS], Google Scholar33https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXnslGhsb4%253D&md5=c9aecbe553ce2d32c4725214e574f7c5The mechanism of action of topiramatePatsalos, Philip N.Reviews in Contemporary Pharmacotherapy (1999), 10 (3), 147-153CODEN: RCPHFW; ISSN:0954-8602. (Marius Press)A review with ∼55 refs. As epilepsy is one of the most prominent serious neurol. conditions, affecting about 50 million people world-wide, of whom 20% are pharmacol. intractable, there has been substantial interest in developing new antiepileptic drugs. Since 1989 eight new antiepileptic drugs have been licensed world-wide. Topiramate, a sulfamate-substituted monosaccharide, was licensed in the UK in 1995 as adjunctive therapy in patients with intractable partial epilepsy. Clin. evidence suggests that topiramate is a potent antiepileptic drug with a broad spectrum of activity and corroborates the significant efficacy obsd. in predictive animal models of epilepsy, i.e., maximal electroshock, i.v. pentylenetetrazole, genetic (spontaneous epileptic rat and DBA/2 mouse) and amygdala kindling models. Pharmacol. evidence indicates that topiramate may act via several mechanisms including: modulation of voltage-dependent sodium channels, potentiation of γ-aminobutyric acid (GABA) inhibition, block of excitatory neurotransmission, and possibly modulation of voltage- and receptor-gated calcium ion channels. Topiramate not only prevents seizure spread but it also elevates seizure threshold. Carbonic anhydrase inhibiting properties have also been demonstrated but they are not considered to be relevant to anticonvulsant activity. This combination of pharmacol. properties is unique amongst currently available antiepileptic drugs and may explain why topiramate is effective in both partial and generalized seizures, and why it is proving efficacious in numerous intractable syndromic epilepsies.
- 34(a) Monteiro, J.; Alves, M. G.; Oliveira, P. F.; Silva, B. M. Pharmacological potential of methylxanthines: Retrospective analysis and future expectations. Crit. Rev. Food Sci. Nutr. 2019, 59, 2597– 2625, DOI: 10.1080/10408398.2018.1461607[Crossref], [PubMed], [CAS], Google Scholar.34ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXpslaksbY%253D&md5=af1ec49bae9b7813e0903b0f8f71c55dPharmacological potential of methylxanthines: Retrospective analysis and future expectationsMonteiro, Joao; Alves, Marco G.; Oliveira, Pedro F.; Silva, Branca M.Critical Reviews in Food Science and Nutrition (2019), 59 (16), 2597-2625CODEN: CRFND6; ISSN:1040-8398. (Taylor & Francis, Inc.)Methylated xanthines (methylxanthines) are available from a significant no. of different botanical species. They are ordinarily included in daily diet, in many extremely common beverages and foods. Caffeine, theophylline and theobromine are the main methylxanthines available from natural sources. The supposedly relatively low toxicity of methylxanthines, combined with the many beneficial effects that have been attributed to these compds. through time, generated a justified attention and a very prolific ground for dedicated scientific reports. Methylxanthines have been widely used as therapeutical tools, in an intriguing range of medicinal scopes. In fact, methylxanthines have been/were medically used as Central Nervous System stimulants, bronchodilators, coronary dilators, diuretics and anti-cancer adjuvant treatments. Other than these applications, methylxanthines have also been hinted to hold other beneficial health effects, namely regarding neurodegenerative diseases, cardioprotection, diabetes and fertility. However, it seems now consensual that toxicity concerns related to methylxanthine consumption and/or therapeutic use should not be dismissed. Taking all the knowledge and expectations on the potential of methylxanthines into account, we propose a systematic look at the past and future of methylxanthine pharmacol. applications, discussing all the promise and anticipating possible constraints. Anyways, methylxanthines will still substantiate considerable meaningful research and discussion for years to come.(b) Matera, M. G.; Page, C. P.; Calzetta, L.; Rogliani, P.; Cazzola, M. Pharmacology and therapeutics of bronchodilators revisited. Pharmacol. Rev. 2020, 72, 218– 252, DOI: 10.1124/pr.119.018150[Crossref], [PubMed], [CAS], Google Scholar34bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXitFGitbzF&md5=f60fcee4ec5622bddb815d2250523ec9Pharmacology and therapeutics of bronchodilators revisitedMatera, M. G.; Page, C. P.; Calzetta, L.; Rogliani, P.; Cazzola, M.Pharmacological Reviews (2020), 72 (1), 218-252CODEN: PAREAQ; ISSN:1521-0081. (American Society for Pharmacology and Experimental Therapeutics)Bronchodilators remain the cornerstone of the treatment of airway disorders such as asthma and chronic obstructive pulmonary disease (COPD). How to optimize the use of our existing classes of bronchodilator and in identifying novel classes of bronchodilator drugs. Recent research has shown that optimization of bronchodilation occurs when both arms of the autonomic nervous system are affected through antagonism of muscarinic receptors to reduce the influence of parasympathetic innervation of the lung and through stimulation of b2-adrenoceptors (b2-ARs) on airway smooth muscle with b2-AR-selective agonists to mimic the sympathetic influence on the lung. This is currently achieved by use of fixed-dose combinations of inhaled long-acting b2-adrenoceptor agonists (LABAs) and long-acting muscarinic acetylcholine receptor antagonists (LAMAs). Due to the distinct mechanisms of action of LAMAs and LABAs, the additive/synergistic effects of using these drug classes together has been extensively investigated. More recently, so-called "triple inhalers" contg. fixed-dose combinations of both classes of bronchodilator (dual bronchodilation) and an inhaled corticosteroid in the same inhaler have been developed. Furthermore, a no. of so-called "bifunctional drugs" having two different primary pharmacol. actions in the same mol. are under development. This review discusses recent advancements in knowledge on bronchodilators and bifunctional drugs for the treatment of asthma and COPD.
- 35(a) Shukla, D.; Chakraborty, S.; Singh, S.; Mishra, B. Doxofylline: a promising methylxanthine derivative for the treatment of asthma and chronic obstructive pulmonary disease. Expert Opin. Pharmacother. 2009, 10, 2343– 2356, DOI: 10.1517/14656560903200667[Crossref], [PubMed], [CAS], Google Scholar.35ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtFCgtLfK&md5=172dae88895bbac0ff31bd5e468ee4edDoxofylline: a promising methylxanthine derivative for the treatment of asthma and chronic obstructive pulmonary diseaseShukla, Dali; Chakraborty, Subhashis; Singh, Sanjay; Mishra, BrahmeshwarExpert Opinion on Pharmacotherapy (2009), 10 (14), 2343-2356CODEN: EOPHF7; ISSN:1465-6566. (Informa Healthcare)A review. Doxofylline, a methylxanthine deriv., has recently drawn attention because of its better safety profile and similar efficacy over the most widely prescribed analog, theophylline, indicated for asthma and chronic obstructive pulmonary disease. This article attempts to discuss the pharmacodynamics/pharmacokinetics and clin. efficacy of doxofylline. An extensive search in three electronic databases (Unbound Medline, Pubmed and Sciencedirect) and internet search engines (Scirus and Google Scholar) were used to identify the clin. studies on doxofylline. The literature search was carried out without time constraints to ensure max. coverage of existing literature on doxofylline. In a relatively large no. of comparative studies, doxofylline is indicated to have less affinity for α1 and α2 receptors than theophylline. Unlike theophylline, doxofylline does not antagonize calcium channels, nor does it interfere with the influx of calcium into the cells, which probably reduces the cardiac side effects. Moreover, it does not affect sleep rhythm, gastric secretions, heart rate and rhythm and CNS functioning. Numerous reports available regarding the better tolerability of doxofylline than theophylline prove it as a potential bronchodilator with promising pharmacol. behavior. However, despite its superior safety and clin. efficacy, the potential of doxofylline has not been fully exploited.(b) Matera, M. G.; Page, C.; Cazzola, M. Doxofylline is not just another theophylline!. Int. J. Chronic Obstruct. Pulm. Dis. 2017, 12, 3487– 3493, DOI: 10.2147/COPD.S150887[Crossref], [PubMed], [CAS], Google Scholar35bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXntVKnsb4%253D&md5=5d94dfedf43b6ebab35b7858f12984e8Doxofylline is not just another theophylline!Matera, Maria Gabriella; Page, Clive; Cazzola, MarioInternational Journal of Chronic Obstructive Pulmonary Disease (2017), 12 (), 3487-3493CODEN: IJCOC3; ISSN:1178-2005. (Dove Medical Press Ltd.)Doxofylline, which differs from theophylline in contg. the dioxalane group at position 7, has comparable efficacy to theophylline in the treatment of respiratory diseases, but with an improved tolerability profile and a favorable risk-to-benefit ratio. Furthermore, it does not have significant drug-drug interactions as exhibited with theophylline, which make using theophylline more challenging, esp. in elderly patients with co-morbidities receiving multiple classes of drug. It is now clear that doxofylline also possesses a distinct pharmacol. profile from theophylline (no significant effect on any of the known phosphodiesterase isoforms, no significant adenosine receptor antagonism, no direct effect on histone deacetylases, interaction with β2-adrenoceptors) and therefore, should not be considered as just a modified theophylline. Randomized clin. trials of doxofylline to investigate the use of this drug to reduce exacerbations and hospitalizations due to asthma or COPD as an alternative to expensive biologics, and certainly as an alternative to theophylline are to be encouraged.
- 36(a) Zhao, X.; Ma, H.; Pan, Q.; Wang, H.; Qian, X.; Song, P.; Zou, L.; Mao, M.; Xia, S.; Ge, G.; Yang, L. Theophylline acetaldehyde as the initial product in doxophylline metabolism in human liver. Drug Metab. Dispos. 2020, 48, 345– 352, DOI: 10.1124/dmd.119.089565[Crossref], [PubMed], [CAS], Google Scholar.36ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtVeqsbzO&md5=9464366706ab683a792e0ee28e56be05Theophylline acetaldehyde as the initial product in doxophylline metabolism in human liverZhao, Xiaohua; Ma, Hong; Pan, Qiusha; Wang, Haiyi; Qian, Xingkai; Song, Peifang; Zou, Liwei; Mao, Mingqing; Xia, Shuyue; Ge, Guangbo; Yang, LingDrug Metabolism & Disposition (2020), 48 (5), 345-352CODEN: DMDSAI; ISSN:1521-009X. (American Society for Pharmacology and Experimental Therapeutics)In this study, the metabolites of DOXO were characterized. A total of nine metabolites of DOXO were identified in vitro using liver microsomes from human and four other animal species. Among them, six metabolites were reported for the first time. The top three metabolites were theophylline acetaldehyde (M1), theophylline-7-acetic acid (M2), and etophylline (M4). A comparative anal. of DOXO metabolismin human using liver microsomes, S9 fraction, and plasma samples demonstrated the following: 1) The metab. of DOXO began with a cytochrome P 450 (P 450)-mediated, rate-limiting step at the C ring and produced M1, the most abundant metabolite in human liver microsomes. However, in human plasma, the M1 prodn. was rather low. 2) M1 was further converted to M2 and M4, the end products of DOXO metab. in vivo, by non-P 450 dismutase in the cytosol. This dismutation process also relied on the ratio of NADP+/NADPH in the cell. These findings for the first time elucidated the metabolic sites and routes of DOXO metab. in human. SIGNIFICANCE STATEMENT We systematically characterized doxophylline metab. using in vitro and in vivo assays. Our findings evolved the understandings of metabolic sites and pathways for methylxanthine derivs. with the aldehyde functional group.(b) Grosa, G.; Franzone, J. S.; Biglino, G. Metabolism of doxophylline by rat liver microsomes. Drug Metab. Dispos. 1986, 14, 267– 270[PubMed], [CAS], Google Scholar36bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL28XitFymtrY%253D&md5=18b758d2873af115bb42d57cd58f78caMetabolism of doxophylline by rat liver microsomesGrosa, G.; Franzone, J. S.; Biglino, G.Drug Metabolism and Disposition (1986), 14 (2), 267-70CODEN: DMDSAI; ISSN:0090-9556.The metabolic transformation of the bronchospasmolytic agent doxophylline (I) [69975-86-6] was studied in vitro with phenobarbital-induced rat liver microsomal fraction contg. the NADPH-generating system. Doxophylline was poorly metabolized as 95% of the recovered material was parent compd. The major metabolite was 2'-hydroxyethyl ester of theophylline acetic acid [61379-38-2]. Theophylline [58-55-9] was a minor metabolite. The per cent ratio of the two metabolites was 4:1. Doxophylline appears to undergo a regiospecific metab. on the N7 side chain.
- 37Griebel, G.; Stemmelin, J.; Lopez-Grancha, M.; Fauchey, V.; Slowinski, F.; Pichat, P.; Dargazanli, G.; Abouabdellah, A.; Cohen, C.; Bergis, O. E. The selective reversible FAAH inhibitor, SSR411298, restores the development of maladaptive behaviors to acute and chronic stress in rodents. Sci. Rep. 2018, 8, 2416, DOI: 10.1038/s41598-018-20895-z[Crossref], [PubMed], [CAS], Google Scholar37https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1MvnsF2mtQ%253D%253D&md5=924080603c7791f41ef83e9d8890fcb5The selective reversible FAAH inhibitor, SSR411298, restores the development of maladaptive behaviors to acute and chronic stress in rodentsGriebel Guy; Stemmelin Jeanne; Lopez-Grancha Mati; Fauchey Valerie; Slowinski Franck; Dargazanli Gihad; Abouabdellah Ahmed; Pichat Philippe; Cohen Caroline; Bergis Olivier EScientific reports (2018), 8 (1), 2416 ISSN:.Enhancing endogenous cannabinoid (eCB) signaling has been considered as a potential strategy for the treatment of stress-related conditions. Fatty acid amide hydrolase (FAAH) represents the primary degradation enzyme of the eCB anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). This study describes a potent reversible FAAH inhibitor, SSR411298. The drug acts as a selective inhibitor of FAAH, which potently increases hippocampal levels of AEA, OEA and PEA in mice. Despite elevating eCB levels, SSR411298 did not mimic the interoceptive state or produce the behavioral side-effects (memory deficit and motor impairment) evoked by direct-acting cannabinoids. When SSR411298 was tested in models of anxiety, it only exerted clear anxiolytic-like effects under highly aversive conditions following exposure to a traumatic event, such as in the mouse defense test battery and social defeat procedure. Results from experiments in models of depression showed that SSR411298 produced robust antidepressant-like activity in the rat forced-swimming test and in the mouse chronic mild stress model, restoring notably the development of inadequate coping responses to chronic stress. This preclinical profile positions SSR411298 as a promising drug candidate to treat diseases such as post-traumatic stress disorder, which involves the development of maladaptive behaviors.
- 38Garde, D. J&J halts a depression program in the shadow of a fatal French trial. https://www.fiercebiotech.com/r-d/j-j-halts-a-depression-program-shadow-of-a-fatal-french-trial (accessed March 17, 2021).
- 39Belema, M.; Meanwell, N. A. Discovery of daclatasvir, a pan-genotypic hepatitis C virus NS5A replication complex inhibitor with potent clinical effect. J. Med. Chem. 2014, 57, 5057– 5071, DOI: 10.1021/jm500335h[ACS Full Text], [CAS], Google Scholar39https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXmsFWgurs%253D&md5=1428746b49ba356ce6993a58b143e5dcDiscovery of Daclatasvir, a Pan-Genotypic Hepatitis C Virus NS5A Replication Complex Inhibitor with Potent Clinical EffectBelema, Makonen; Meanwell, Nicholas A.Journal of Medicinal Chemistry (2014), 57 (12), 5057-5071CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. The discovery and development of the first-in-class hepatitis C virus (HCV) NS5A replication complex inhibitor daclatasvir provides a compelling example of the power of phenotypic screening to identify leads engaging novel targets in mechanistically unique ways. HCV NS5A replication complex inhibitors are pan-genotypic in spectrum, and this mechanistic class provides the most potent HCV inhibitors in vitro that have been described to date. Clin. trials with daclatasvir demonstrated a potent effect on reducing plasma viral load and, in combination with mechanistically orthogonal HCV inhibitors, established the ability to cure even the most difficult infections without the need for immune stimulation. In this Drug Annotation, the authors describe the discovery of the original high-throughput screening lead BMS-858 and the chem. conundrum and challenges resolved in optimizing to daclatasvir as a clin. candidate and finally the authors summarize the results of select clin. studies.
- 40(a) Kazmierski, W. W.; Maynard, A.; Duan, M.; Baskaran, S.; Botyanszki, J.; Crosby, R.; Dickerson, S.; Tallant, M.; Grimes, R.; Hamatake, R.; Leivers, M.; Roberts, C. D.; Walker, J. Novel spiroketal pyrrolidine GSK2336805 potently inhibits key hepatitis C virus genotype 1b mutants: from lead to clinical compound. J. Med. Chem. 2014, 57, 2058– 2073, DOI: 10.1021/jm4013104[ACS Full Text.], [CAS], Google Scholar40ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXjt1ynurw%253D&md5=630673e83d4360ea66b420287feb5451Novel Spiroketal Pyrrolidine GSK2336805 Potently Inhibits Key Hepatitis C Virus Genotype 1b Mutants: From Lead to Clinical CompoundKazmierski, Wieslaw M.; Maynard, Andrew; Duan, Maosheng; Baskaran, Sam; Botyanszki, Janos; Crosby, Renae; Dickerson, Scott; Tallant, Matthew; Grimes, Rick; Hamatake, Robert; Leivers, Martin; Roberts, Christopher D.; Walker, JillJournal of Medicinal Chemistry (2014), 57 (5), 2058-2073CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Rapid clin. progress of hepatitis C virus (HCV) replication inhibitors, including these selecting for resistance in the NS5A region (NS5A inhibitors), promises to revolutionize HCV treatment. Herein, we describe our explorations of diverse spiropyrrolidine motifs in novel NS5A inhibitors and a proposed interaction model. We discovered that the 1,4-dioxa-7-azaspiro[4.4]nonane motif in inhibitor 41H (I, GSK2236805) supported high potency against genotypes 1a and 1b as well as in genotype 1b L31V and Y93H mutants. Consistent with this, 41H potently suppressed HCV RNA in the 20-day RNA redn. assay. Pharmacokinetic and safety data supported further progression of 41H to the clinic.(b) Wilfret, D. A.; Walker, J.; Adkison, K. K.; Jones, L. A.; Lou, Y.; Gan, J.; Castellino, S.; Moseley, C. L.; Horton, J.; de Serres, M.; Culp, A.; Goljer, I.; Spreen, W. Safety, tolerability, pharmacokinetics, and antiviral activity of GSK2336805, an inhibitor of hepatitis C virus (HCV) NS5A, in healthy subjects and subjects chronically infected with HCV genotype 1. Antimicrob. Agents Chemother. 2013, 57, 5037– 5044, DOI: 10.1128/AAC.00910-13[Crossref], [PubMed], [CAS], Google Scholar40bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVygtLfN&md5=8e9f3eee73c0e688f1dae5510f3c1fc7Safety, tolerability, pharmacokinetics, and antiviral activity of GSK2336805, an inhibitor of hepatitis C virus (HCV) NS5A, in healthy subjects and subjects chronically infected with HCV genotype 1Wilfret, D. A.; Walker, J.; Adkison, K. K.; Jones, L. A.; Lou, Y.; Gan, J.; Castellino, S.; Moseley, C. L.; Horton, J.; de Serres, M.; Culp, A.; Goljer, I.; Spreen, W.Antimicrobial Agents and Chemotherapy (2013), 57 (10), 5037-5044CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)GSK2336805 is an orally bioavailable hepatitis C virus (HCV) inhibitor working through an NS5A-mediated mechanism. This first-time-in-human study was conducted to assess the safety, tolerability, pharmacokinetics, metab., and efficacy of GSK2336805 in healthy subjects and subjects infected with HCV genotype 1. We performed a three-part, randomized, double-blind, placebo-controlled study in 46 healthy subjects and 23 HCV-infected subjects. After an overnight fast, healthy subjects received GSK2336805 as 10 mg, 30 mg, 30 mg plus food, and 60 mg in a single dose and 10 mg (7 days), 30 mg (7 days), and 75 mg (14 days) in a once-daily multiple dose. Subjects with HCV received GSK2336805 as a 1- to 120-mg single dose. In subjects with HCV, redns. in HCV RNA were obsd. within 4 h and a single dose of GSK2336805 of ≥10 mg resulted in a statistically significant ≥2-log redn. in HCV RNA compared with placebo at 24 h postdose. GSK2336805 was readily absorbed in all subjects, and the half-life (t1/2) was suitable for once-daily dosing. Administration of GSK2336805 with food had no effect on plasma GSK2336805 exposure; however, absorption was delayed, with a median tmax (time to max. concn. of drug in serum) of 4.5 vs. 2.0 h. Twenty subjects who received GSK2336805 experienced mild to moderate adverse events; none were serious. GSK2336805 was well tolerated and exhibited rapid, significant antiviral activity after a single dose in HCV-infected subjects. These results support the conduct of further studies evaluating GSK2336805 administered once daily for longer durations in combination with peginterferon, ribavirin, and other direct-acting antivirals.
- 41Tai, V. W.; Garrido, D.; Price, D. J.; Maynard, A.; Pouliot, J. J.; Xiong, Z.; Seal III, J. W.; Creech, K. L.; Kryn, L. H.; Baughman, T. M.; Peat, A. J. Design and synthesis of spirocyclic compounds as HCV replication inhibitors by targeting viral NS4B protein. Bioorg. Med. Chem. Lett. 2014, 24, 2288– 2294, DOI: 10.1016/j.bmcl.2014.03.080[Crossref], [PubMed], [CAS], Google Scholar41https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXmt1Wlu7s%253D&md5=e221782d8c961d7b60348c98d3de0da1Design and synthesis of spirocyclic compounds as HCV replication inhibitors by targeting viral NS4B proteinTai, Vincent W.-F.; Garrido, Dulce; Price, Daniel J.; Maynard, Andrew; Pouliot, Jeffrey J.; Xiong, Zhiping; Seal, John W.; Creech, Katrina L.; Kryn, Luz H.; Baughman, Todd M.; Peat, Andrew J.Bioorganic & Medicinal Chemistry Letters (2014), 24 (10), 2288-2294CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Pyrazolo[1,5-a]pyridinecarbonyl-substituted spiropiperidines such as pyrazolo[1,5-a]pyridinecarbonyl dispirocyclopropanedioxanepiperidinol I and pyrazolo[1,5-a]pyridinecarbonyl hydroxyspiropiperidineoxazolidinone II were prepd. as inhibitors of hepatitis C viral protein NS4B; their inhibition of HCV replicons 1a and 1b and their lack of cytotoxicity in human cells at concns. < 25 μM were detd. Spirocyclic piperidine ketals such as I were prepd. which showed in vitro anti-HCV activities; for example, I showed EC50 of 1.5 nM and 1.2 nM against genotype 1a and 1b replicons, resp., in vitro. Spirocyclic piperidine oxazolidinones such as II were prepd.; II showed EC50 values of 10.9 nM and 6.1 nM against HCV 1a and 1b replicons, resp. The solubilities, permeabilities in the presence of P-gp transporters, half-life, and calcd. lipophilicities, polar surface areas, and lipophilic ligand efficiencies were detd. for selected compds. including I and II. Both I and II bound directly to non-structural NS4B protein in vitro (IC50 values of 10.2 nM and 30.4 nM, resp.); I and II exhibited reduced potency (27-185-fold increases in EC50 values) in replicons contg. resistance mutations encoding changes (H94N and V105M) in the NS4B protein. The structure of a dispirocyclopropanedioxanepiperidine di-O-p-toluoyltartrate salt used in the prepn. of I was detd. by X-ray crystallog.
- 42(a) Chen, K. X.; Njoroge, G.; Arasappan, A.; Venkatraman, S.; Vibulbhan, B.; Yang, W.; Parekh, T. N.; Pichardo, J.; Prongay, A.; Cheng, K.; Butkiewicz, N.; Yao, N.; Madison, V.; Girijavallabhan, V. Novel potent hepatitis C virus NS3 serine protease inhibitors derived from proline-based macrocycles. J. Med. Chem. 2006, 49, 995– 1005, DOI: 10.1021/jm050820s[ACS Full Text.], [CAS], Google Scholar42ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XitV2mtQ%253D%253D&md5=113c44a06c8018697ee83ae8614b6a95Novel Potent Hepatitis C Virus NS3 Serine Protease Inhibitors Derived from Proline-Based MacrocyclesChen, Kevin X.; Njoroge, F. George; Arasappan, Ashok; Venkatraman, Srikanth; Vibulbhan, Bancha; Yang, Weiying; Parekh, Tejal N.; Pichardo, John; Prongay, Andrew; Cheng, Kuo-Chi; Butkiewicz, Nancy; Yao, Nanhua; Madison, Vincent; Girijavallabhan, ViyyoorJournal of Medicinal Chemistry (2006), 49 (3), 995-1005CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The hepatitis C virus (HCV) NS3 protease is essential for viral replication. It has been a target of choice for intensive drug discovery research. On the basis of an active pentapeptide inhibitor, I, we envisioned that macrocyclization from the P2 proline to P3 capping could enhance binding to the backbone Ala156 residue and the S4 pocket. Thus, a no. of P2 proline-based macrocyclic α-ketoamide inhibitors were prepd. and investigated in an HCV NS3 serine protease continuous assay (Ki*). The biol. activity varied substantially depending on factors such as the ring size, no. of amino acid residues, no. of Me substituents, type of heteroatom in the linker, P3 residue, and configuration at the proline C-4 center. The pentapeptide inhibitors were very potent, with the C-terminal acids and amides being the most active ones [II; R = H, R1 = cyclohexyl, R2 = NH-Gly-Phg-NMe2 (24), Ki* = 8 nM]. The tetrapeptides and tripeptides were less potent. Sixteen- and seventeen-membered macrocyclic compds. were equally potent, while fifteen-membered analogs were slightly less active. Gem-Di-Me substituents at the linker improved the potency of all inhibitors [the best compd. was II (R = Me, R1 = cyclohexyl, R2 = NH-Gly-Phg-NMe2) (45), Ki* = 6 nM]. The combination of tert-leucine at P3 and di-Me substituents at the linker in compd. II (R = Me, R1 = t-Bu, R2 = NH-Gly-Phg-NMe2) realized a selectivity of 307 against human neutrophil elastase. Compd. 45 had an IC50 of 130 nM in a cellular replicon assay, while IC50 for 24 was 400 nM. Several compds. had excellent s.c. AUC and bioavailability in rats. Although tripeptide compd. II (R = Me, R1 = cyclohexyl, R2 = NH-allyl) was 97% orally bioavailable, larger pentapeptides generally had low oral bioavailability. The X-ray crystal structure of compds. 24 and 45 bound to the protease demonstrated the close interaction of the macrocycle with the Ala156 Me group and S4 pocket. The strategy of macrocyclization has been proved to be successful in improving potency (>20-fold greater than that of I) and in structural depeptization.(b) Chen, K. X.; Njoroge, F. G.; Vibulbhan, B.; Prongay, A.; Pichardo, J.; Madison, V.; Buevich, A.; Chan, T. M. Proline-based macrocyclic inhibitors of the hepatitis C virus: stereoselective synthesis and biological activity. Angew. Chem., Int. Ed. 2005, 44, 7024– 7028, DOI: 10.1002/anie.200501553[Crossref], [CAS], Google Scholar42bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXht1KrsrjJ&md5=95822f091507b7daae129462cc641611Proline-based macrocyclic inhibitors of the hepatitis C virus: Stereoselective synthesis and biological activityChen, Kevin X.; Njoroge, F. George; Vibulbhan, Bancha; Prongay, Andrew; Pichardo, John; Madison, Vincent; Buevich, Alexei; Chan, Tze-MingAngewandte Chemie, International Edition (2005), 44 (43), 7024-7028CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)Macrocyclization through a Mitsunobu reaction was used to synthesize a 17-membered macrocycle. The bicyclic acetal core was prepd. completely diastereoselectively. For example, macrocycles I (R = OBu-t, OH, NMe2) were prepd. The macrocyclic peptidomimetic surrogate of the P2-P3 dipeptide moiety was designed to function as a hepatitis C virus (HCV) NS3 serine protease inhibitor, and the pentapeptide α-ketoamides derived from the macrocycle were shown to be potent HCV inhibitors.
- 43(a) Sanglier, J.-J.; Quesniaux, V.; Fehr, T.; Hofmann, H.; Mahnke, M.; Memmert, K.; Schuler, W.; Zenke, G.; Gschwind, L.; Maurer, C.; Schilling, W. Sanglifehrins A, B, C and D, novel cyclophilin-binding compounds isolated from Streptomyces sp. A92–308110: I. Taxonomy, fermentation, isolation and biological activity. J. Antibiot. 1999, 52, 466– 473, DOI: 10.7164/antibiotics.52.466[Crossref], [PubMed], [CAS], Google Scholar.43ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXjs1yhsbc%253D&md5=a8627873fed55ee57f2aa8ecd1cf58eeSanglifehrins A, B, C and D, novel cyclophilin-binding compounds isolated from Streptomyces sp. A92-308110: I. Taxonomy, fermentation, isolation and biological activitySanglier, Jean-Jacques; Quesniaux, Valerie; Fehr, Theodor; Hofmann, Hans; Mahnke, Marion; Memmert, Klaus; Schuler, Walter; Zenke, Gerhard; Gschwind, Liliane; Maurer, Claudine; Schilling, WolfgangJournal of Antibiotics (1999), 52 (5), 466-473CODEN: JANTAJ; ISSN:0021-8820. (Japan Antibiotics Research Association)A novel class of macrolides for which the name sanglifehrins is proposed has been discovered from actinomycete strains based on their high affinity binding for cyclophilin A (CypA), an immunophilin originally identified as a cytosolic protein binding cyclosporin A (CsA). The sanglifehrins were produced by Streptomyces sp. A92-308110. They were isolated and purified by extn. and several chromatog. activity-guided steps. Sanglifehrins A and B (I and II, resp., where R=A) exhibit a 10∼20 fold higher affinity for CypA than CsA, whereas the affinity of sanglifehrins C and D (III and IV, resp., where R=B) for CypA is comparable to that of CsA. Sanglifehrins exhibit a lower immunosuppressive activity than CsA when tested in the mixed lymphocyte reaction. Their in vitro activity indicates that they belong to a novel class of immunosuppressants.(b) Fehr, T.; Kallen, J.; Oberer, L.; Sanglier, J.-J.; Schilling, W. Sanglifehrins A, B, C and D, novel cyclophilin-binding compounds isolated from Streptomyces sp. A92–308110: II. Structure elucidation, stereochemistry and physico-chemical properties. J. Antibiot. 1999, 52, 474– 479, DOI: 10.7164/antibiotics.52.474[Crossref], [PubMed], [CAS], Google Scholar43bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXjs1yhtr4%253D&md5=36f9eb7ae761ad51a5a62bdccd1c4864Sanglifehrins A, B, C and D, novel cyclophilin-binding compounds isolated from Streptomyces sp. A92-308110: II. Structure elucidation, stereochemistry and physico-chemical propertiesFehr, Theodor; Kallen, Jorg; Oberer, Lukas; Sanglier, Jean-Jacques; Schilling, WolfgangJournal of Antibiotics (1999), 52 (5), 474-479CODEN: JANTAJ; ISSN:0021-8820. (Japan Antibiotics Research Association)A novel class of macrolides, the sanglifehrins, was discovered by screening of actinomycete strains with a cyclophilin-binding assay. The chem. structures and abs. stereochemistries of the sanglifehrins A, B, C and D were detd. unambiguously by NMR-techniques and by X-ray crystallog. of the complex with cyclophilin A. Sanglifehrin A consists of a 22-membered macrocycle contg. a tripeptide subunit and features in position 23 a chain of nine carbon atoms bearing a spirocyclic substituent. Sanglifehrins A and B are genuine metabolites whereas sanglifehrins C and D are artifacts.
- 44Mackman, R.; Steadman, V. A.; Dean, D. K.; Jansa, P.; Poullennec, K. G.; Appleby, T.; Austin, C.; Blakemore, C. A.; Cai, R.; Cannizzaro, C.; Chin, G.; Chiva, J. C.; Dunbar, N. A.; Fliri, H.; Highton, A. J.; Hui, H.; Ji, M.; Jin, H.; Karki, K.; Keats, A. J.; Lazarides, L.; Lee, Y.; Liclican, A.; Mish, M.; Murray, B.; Pettit, S. B.; Yun, P.; Sangi, M.; Santos, R.; Sanvoisin, J.; Schmitz, U.; Schrier, A.; Siegel, D.; Sperandio, D.; Stepan, G.; Tian, Y.; Watt, G. M.; Yang, H.; Schultz, B. E. Discovery of a potent and orally bioavailable cyclophilin inhibitor derived from the sanglifehrin macrocycle. J. Med. Chem. 2018, 61, 9473– 9499, DOI: 10.1021/acs.jmedchem.8b00802[ACS Full Text], [CAS], Google Scholar44https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsVChtbrI&md5=616cf72e0d2766e159769166c98a9e86Discovery of a potent and orally bioavailable cyclophilin inhibitor derived from the sanglifehrin macrocycleMackman, Richard L.; Steadman, Victoria A.; Dean, David K.; Jansa, Petr; Poullennec, Karine G.; Appleby, Todd; Austin, Carol; Blakemore, Caroline A.; Cai, Ruby; Cannizzaro, Carina; Chin, Gregory; Chiva, Jean-Yves C.; Dunbar, Neil A.; Fliri, Hans; Highton, Adrian J.; Hui, Hon; Ji, Mingzhe; Jin, Haolun; Karki, Kapil; Keats, Andrew J.; Lazarides, Linos; Lee, Yu-Jen; Liclican, Albert; Mish, Michael; Murray, Bernard; Pettit, Simon B.; Pyun, Peter; Sangi, Michael; Santos, Rex; Sanvoisin, Jonathan; Schmitz, Uli; Schrier, Adam; Siegel, Dustin; Sperandio, David; Stepan, George; Tian, Yang; Watt, Gregory M.; Yang, Hai; Schultz, Brian E.Journal of Medicinal Chemistry (2018), 61 (21), 9473-9499CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Cyclophilins are a family of peptidyl-prolyl isomerases that are implicated in a wide range of diseases including hepatitis C. Our aim was to discover through total synthesis an orally bioavailable, non-immunosuppressive cyclophilin (Cyp) inhibitor with potent anti-hepatitis C virus (HCV) activity that could serve as part of an all oral antiviral combination therapy. An initial lead (I) derived from the sanglifehrin A macrocycle was optimized using structure based design to produce a potent and orally bioavailable inhibitor (II). The macrocycle ring size was reduced by one atom, and an internal hydrogen bond drove improved permeability and drug-like properties. II demonstrates potent Cyp inhibition (Kd = 5 nM), potent anti-HCV 2a activity (EC50 = 98 nM), and high oral bioavailability in rat (100%) and dog (55%). The synthetic accessibility and properties of II support its potential as an anti-HCV agent and for interrogating the role of Cyp inhibition in a variety of diseases.
- 45Ma, X.; Idle, J. R.; Gonzalez, F. J. The pregnane X receptor: from bench to bedside. Expert Opin. Drug Metab. Toxicol. 2008, 4, 895– 908, DOI: 10.1517/17425255.4.7.895[Crossref], [PubMed], [CAS], Google Scholar45https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXos1Chur0%253D&md5=d485d79dfef46f99ab106007ab32993aThe pregnane X receptor: from bench to bedsideMa, Xiaochao; Idle, Jeffrey R.; Gonzalez, Frank J.Expert Opinion on Drug Metabolism & Toxicology (2008), 4 (7), 895-908CODEN: EODMAP; ISSN:1742-5255. (Informa Healthcare)A review. The pregnane X receptor (PXR; NR1I2), a member of the nuclear receptor superfamily, regulates the expression of metabolic enzymes and transporters involved in the response of mammals to their chem. environment. To summarize the functions and clin. implications of PXR. In the current review, the clin. implications of PXR are discussed, and the use of genetically engineered PXR mouse models is highlighted. Recent advances in mouse models, including Pxr-null and PXR-humanized mice, provide in vivo tools for evaluating the physiol. functions of PXR and its role in controlling xenobiotic metab. and transport. By using the PXR knockout and humanized mouse models, PXR was found to influence drug-drug interactions, hepatic steatosis, and the homeostasis of vitamin D, bile acids, and steroid hormones. PXR was also shown to influence inflammatory bowel diseases.
- 46Wang, Y.; Zhao, H.; Brewer, J. T.; Li, H.; Lao, Y.; Amberg, W.; Behl, B.; Akritopoulou-Zanze, I.; Dietrich, J.; Lange, U. E.; Pohlki, F.; Hoft, C.; Hornberger, W.; Djuric, S. W.; Sydor, J.; Mezler, M.; Relo, A. L.; Vasudevan, A. De novo design, synthesis, and biological evaluation of 3,4-disubstituted pyrrolidine sulfonamides as potent and selective glycine transporter 1 competitive inhibitors. J. Med. Chem. 2018, 61, 7486– 7502, DOI: 10.1021/acs.jmedchem.8b00295[ACS Full Text], [CAS], Google Scholar46https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXht1Cqu7jN&md5=8ccceff336374f790949111b56737d3cDe Novo Design, Synthesis, and Biological Evaluation of 3,4-Disubstituted Pyrrolidine Sulfonamides as Potent and Selective Glycine Transporter 1 Competitive InhibitorsWang, Ying; Zhao, Hongyu; Brewer, Jason T.; Li, Huanqiu; Lao, Yanbin; Amberg, Willi; Behl, Berthold; Akritopoulou-Zanze, Irini; Dietrich, Justin; Lange, Udo E. W.; Pohlki, Frauke; Hoft, Carolin; Hornberger, Wilfried; Djuric, Stevan W.; Sydor, Jens; Mezler, Mario; Relo, Ana Lucia; Vasudevan, AnilJournal of Medicinal Chemistry (2018), 61 (17), 7486-7502CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The development of glycine transporter 1 (GlyT1) inhibitors may offer putative treatments for schizophrenia and other disorders assocd. with hypofunction of the glutaminergic N-methyl-D-aspartate (NMDA) receptor. Herein, we describe the synthesis and biol. evaluation of a series of 3,4-disubstituted pyrrolidine sulfonamides as competitive GlyT1 inhibitors that arose from de novo scaffold design. Relationship of chem. structure to drug-drug interaction (DDI) and bioactivation was mechanistically investigated. Murine studies were strategically incorporated into the screening funnel to provide early assessments of in vivo target occupancy (TO) by ex vivo binding studies. Advanced compds. derived from iterative structure-activity relationship (SAR) studies possessed high potency in ex vivo binding studies and good brain penetration, promising preliminary in vivo efficacy, acceptable preclin. pharmacokinetics, and manageable DDI and bioactivation liabilities.
- 47(a) Lovering, F.; Bikker, J.; Humblet, C. Escape from flatland: increasing saturation as an approach to improving clinical success. J. Med. Chem. 2009, 52, 6752– 6756, DOI: 10.1021/jm901241e[ACS Full Text.], [CAS], Google Scholar47ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXht1KjtLvN&md5=4ca92c30c17c53d77ad376719bad951eEscape from Flatland: Increasing Saturation as an Approach to Improving Clinical SuccessLovering, Frank; Bikker, Jack; Humblet, ChristineJournal of Medicinal Chemistry (2009), 52 (21), 6752-6756CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The medicinal chem. community has become increasingly aware of the value of tracking calcd. phys. properties such as mol. wt., topol. polar surface area, rotatable bonds, and hydrogen bond donors and acceptors. The authors hypothesized that the shift to high-throughput synthetic practices over the past decade may be another factor that may predispose mols. to fail by steering discovery efforts toward achiral, arom. compds. The authors have proposed two simple and interpretable measures of the complexity of mols. prepd. as potential drug candidates. The first is carbon bond satn. as defined by fraction Sp3 (Fsp3) where Fsp3 = (no. of Sp3 hybridized carbons/total carbon count). The second is simply whether a chiral carbon exists in the mol. The authors demonstrate that both complexity (as measured by Fsp3) and the presence of chiral centers correlate with success as compds. transition from discovery, through clin. testing, to drugs. To explain these observations, the authors further demonstrate that satn. correlates with soly., an exptl. phys. property important to success in the drug discovery setting.(b) Hirata, K.; Kotoku, M.; Seki, N.; Maeba, T.; Maeda, K.; Hirashima, S.; Sakai, T.; Obika, S.; Hori, A.; Hase, Y.; Yamaguchi, T.; Katsuda, Y.; Hata, T.; Miyagawa, N.; Arita, K.; Nomura, Y.; Asahina, K.; Aratsu, Y.; Kamada, M.; Adachi, T.; Noguchi, M.; Doi, S.; Crowe, P.; Bradley, E.; Steensma, R.; Tao, H.; Fenn, M.; Babine, R.; Li, X.; Thacher, S.; Hashimoto, H.; Shiozaki, M. SAR Exploration guided by LE and Fsp3: discovery of a selective and orally efficacious RORδ inhibitor. ACS Med. Chem. Lett. 2016, 7, 23– 27, DOI: 10.1021/acsmedchemlett.5b00253[ACS Full Text], [CAS], Google Scholar47bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhslKlt77P&md5=fc2736f8baafee2084bb3adce7bb1a2eSAR Exploration Guided by LE and Fsp3: Discovery of a Selective and Orally Efficacious RORγ InhibitorHirata, Kazuyuki; Kotoku, Masayuki; Seki, Noriyoshi; Maeba, Takaki; Maeda, Katsuya; Hirashima, Shintaro; Sakai, Takayuki; Obika, Shingo; Hori, Akimi; Hase, Yasunori; Yamaguchi, Takayuki; Katsuda, Yoshiaki; Hata, Takahiro; Miyagawa, Naoki; Arita, Kojo; Nomura, Yukihiro; Asahina, Kota; Aratsu, Yusuke; Kamada, Masafumi; Adachi, Tsuyoshi; Noguchi, Masato; Doi, Satoki; Crowe, Paul; Bradley, Erin; Steensma, Ruo; Tao, Haiyan; Fenn, Morgan; Babine, Robert; Li, Xiaolin; Thacher, Scott; Hashimoto, Hiromasa; Shiozaki, MakotoACS Medicinal Chemistry Letters (2016), 7 (1), 23-27CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)A novel series of RORγ inhibitors was identified starting with the HTS hit compd. 2-(5-(2,3-dihydro-1H-inden-2-yl)-4-ethyl-4-H-1,2,4-triazol-3-ylthio)-N-(naphthalen-1-yl)acetamide. After SAR investigation based on a prospective consideration of two drug-likeness metrics, ligand efficiency (LE) and fraction of Sp3 carbon atoms (Fsp3), significant improvement of metabolic stability as well as redn. of CYP inhibition was obsd., which finally led to discovery of a selective and orally efficacious RORγ inhibitor (3R,4R)-1-acetyl-4-(4-cyclopropyl-5-(cis-3-isobutylcyclobutyl)-4H-1,2,4-triazol-3-yl)-M-(2,4-dimethylphenyl) pyrrolidine-3-carboxamide.
- 48Stojanovic-Radic, Z.; Pejic, M.; Dimitrijevic, M.; Aleksic, A.; Kumar, N. V.; Salehi, B.; Cho, W. C.; Sharifi-Rad, J. Piperine - a major principle of black pepper: a review of its bioactivity and studies. Appl. Sci. 2019, 9, 4270, DOI: 10.3390/app9204270[Crossref], [CAS], Google Scholar48https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXntlKiurg%253D&md5=6f319b1ffffa93cbe7f680b2323763e4Piperine-A major principle of black pepper: a review of its bioactivity and studiesStojanovic-Radic, Zorica; Pejcic, Milica; Dimitrijevic, Marina; Aleksic, Ana; Kumar, Nanjangud V. Anil; Salehi, Bahare; Cho, William C.; Sharifi-Rad, JavadApplied Sciences (2019), 9 (20), 4270CODEN: ASPCC7; ISSN:2076-3417. (MDPI AG)Piperine is the main compd. present in black pepper, and is the carrier of its specific pungent taste, which is responsible for centuries of human dietary utilization and worldwide popularity as a food ingredient. Along with the application as a food ingredient and food preservative, it is used in traditional medicine for many purposes, which has in most cases been justified by modern scientific studies on its biol. effects. It has been confirmed that piperine has many bioactive effects, such as antimicrobial action, as well as many physiol. effects that can contribute to general human health, including immunomodulatory, hepatoprotective, antioxidant, antimetastatic, antitumor, and many other activities. Clin. studies demonstrated remarkable antioxidant, antitumor, and drug availability-enhancing characteristics of this compd., together with immunomodulatory potential. All these facts point to the therapeutic potential of piperine and the need to incorporate this compd. into general health-enhancing medical formulations, as well as into those that would be used as adjunctive therapy in order to enhance the bioavailability of various (chemo)therapeutic drugs.
- 49(a) Bertelsen, K. M.; Venkatakrishnan, K.; von Moltke, L. L.; Obach, R. S.; Greenblatt, D. J. Apparent mechanism-based inhibition of human CYP 2D6 in vitro by paroxetine: comparison with fluoxetine and quinidine. Drug Metab. Dispos. 2003, 31, 289– 293, DOI: 10.1124/dmd.31.3.289[Crossref], [PubMed], [CAS], Google Scholar.49ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXhsFKlt7Y%253D&md5=2336fbc058e49e7b530562809c62ba09Apparent mechanism-based inhibition of human CYP2D6 in vitro by paroxetine: Comparison with fluoxetine and quinidineBertelsen, Kirk M.; Venkatakrishnan, Karthik; Von Moltke, Lisa L.; Obach, R. Scott; Greenblatt, David J.Drug Metabolism and Disposition (2003), 31 (3), 289-293CODEN: DMDSAI; ISSN:0090-9556. (American Society for Pharmacology and Experimental Therapeutics)Paroxetine, a selective serotonin reuptake inhibitor, is a potent inhibitor of cytochrome P 450 2D6 (CYP2D6) activity, but the mechanism of inhibition is not established. To det. whether preincubation affects the inhibition of human liver microsomal dextromethorphan demethylation activity by paroxetine, we used a two-step incubation scheme in which all of the enzyme assay components, minus substrate, are preincubated with paroxetine. The kinetic parameters of inhibition were also estd. by varying the time of preincubation as well as the concn. of inhibitor. From these data, a Kitz-Wilson plot was constructed, allowing the estn. of both an apparent inactivator concn. required for half-maximal inactivation (KI) and the maximal rate const. of inactivation (KINACT) value for this interaction. Preincubation of paroxetine with human liver microsomes caused an approx. 8-fold redn. in the IC50 value (0.34 vs. 2.54 μM). Time-dependent inhibition was demonstrated with an apparent KI of 4.85 μM and an apparent KINACT value of 0.17 min-1. Spectral scanning of CYP2D6 with paroxetine yielded an increase in absorbance at 456 nm suggesting paroxetine inactivation of CYP2D6 via the formation of a metabolite intermediate complex. This pattern is consistent with the metab. of the methylenedioxy substituent in paroxetine; such substituents may produce mechanism-based inactivation of cytochrome P 450 enzymes. In contrast, quinidine and fluoxetine, both of which are inhibitors of CYP2D6 activity, did not exhibit a preincubation-dependent increase in inhibitory potency. These data are consistent with mechanism-based inhibition of CYP2D6 by paroxetine but not by quinidine or fluoxetine.(b) Kamel, E. M.; Lamsabhi, A. M. The quasi-irreversible inactivation of Cytochrome P450 enzymes by paroxetine: A computational approach. Org. Biomol. Chem. 2020, 18, 3334– 3345, DOI: 10.1039/D0OB00529K[Crossref], [PubMed], [CAS], Google Scholar.49bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXmsV2rsbY%253D&md5=8fea1e5717b3d39f5ef42aeb344af8afThe quasi-irreversible inactivation of cytochrome P450 enzymes by paroxetine: a computational approachKamel, Emadeldin M.; Lamsabhi, Al MokhtarOrganic & Biomolecular Chemistry (2020), 18 (17), 3334-3345CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)The mechanism-based inactivation (MBI) of P 450 by paroxetine was investigated by computational anal. The drug-enzyme interactions were figured out through studying energy profiles of three competing mechanisms. The potency of paroxetine as P 450's inhibitor was estd. based on the availability of two active sites for the MBI in the paroxetine structure. The inactivation by the amino site of paroxetine mainly proceeds via the hydrogen atom transfer pathway because of the lower energy demand of its rate detg. step. In addn., the low-spin state is the predominant route in the MBI at the methylenedioxo active site as a result of being rebound barrier-free mechanism. Our comparative investigation showed that inactivation at the secondary amine is thermodynamically more favorable because of the lower energy barrier of the dehydration mechanism of the hydroxylated paroxetine complex than its methylenedioxo counterpart. The results of docking anal. coincided with the outputs of DFT calcns. since the docking pose with the lowest binding affinity is that for conformation with polar interaction between the amino group of paroxetine and the oxo moiety of P 450's active site. Assessment of the mol. dynamics simulations trajectories revealed the favorable interaction of paroxetine with P 450.(c) Zhao, S. X.; Dalvie, D. K.; Kelly, J. M.; Soglia, J. R.; Frederick, K. S.; Smith, E. B.; Obach, R. S.; Kalgutkar, A. S. NADPH-dependent covalent binding of [3H]paroxetine to human liver microsomes and S-9 fractions: identification of an electrophilic quinone metabolite of paroxetine. Chem. Res. Toxicol. 2007, 20, 1649– 1657, DOI: 10.1021/tx700132x[ACS Full Text], [CAS], Google Scholar49chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtFSkurrK&md5=e7d3aa749a419cc87340271eb9b839a0NADPH-Dependent Covalent Binding of [3H]Paroxetine to Human Liver Microsomes and S-9 Fractions: Identification of an Electrophilic Quinone Metabolite of ParoxetineZhao, Sabrina X.; Dalvie, Deepak K.; Kelly, Joan M.; Soglia, John R.; Frederick, Kosea S.; Smith, Evan B.; Obach, R. Scott; Kalgutkar, Amit S.Chemical Research in Toxicology (2007), 20 (11), 1649-1657CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)The primary pathway of clearance of the methylenedioxyphenyl-contg. compd. and selective serotonin reuptake inhibitor paroxetine in humans involves P 450 2D6-mediated demethylenation to a catechol intermediate. The process of demethylenation also results in the mechanism-based inactivation of the P 450 isoenzyme. While the link between P 450 2D6 inactivation and pharmacokinetic interactions of paroxetine with P 450 2D6 substrates has been firmly established, there is a disconnect in terms of paroxetine's excellent safety record despite the potential for bioactivation. In the present study, the authors have systematically assessed the NADPH-dependent covalent binding of [3H]paroxetine to human liver microsomes and S-9 prepns. in the absence and presence of cofactors of the various phase II drug-metabolizing enzymes involved in the downstream metab./detoxification of the putative paroxetine-catechol intermediate. Incubation of [3H]paroxetine with human liver microsomes and S-9 prepns. resulted in irreversible binding of radioactive material to macromols. by a process that was NADPH-dependent. The addn. of reduced glutathione (GSH) to the microsomal and S-9 incubations resulted in a dramatic redn. of covalent binding. Following incubations with NADPH- and GSH-supplemented human liver microsomes and S-9, three sulfhydryl conjugates with MH+ ions at 623 Da (GS1), 779 Da (GS2), and 928 Da (GS3), resp., were detected by LC-MS/MS. The collision-induced dissocn. spectra allowed an insight into the structure of the GSH conjugates, based on which, bioactivation pathways were proposed. The formation of GS1 was consistent with Michael addn. of GSH to the quinone derived from two-electron oxidn. of paroxetine-catechol. GS3 was formed by the addn. of a second mol. of GSH to the quinone species obtained via the two-electron oxidn. of GS1. The mechanism of formation of GS2 can be rationalized via (i) further two-electron oxidn. of the catechol motif in GS3 to the ortho-quinone, (ii) loss of a glutamic acid residue from one of the adducted GSH mols., and (iii) condensation of a cysteine-NH2 with an adjacent carbonyl of the ortho-quinone to yield an ortho-benzoquinoneimine structure. Inclusion of the catechol-O-methyltransferase cofactor S-adenosylmethionine (SAM) in S-9 incubations also dramatically reduced the covalent binding of [3H]paroxetine, a finding that was consistent with O-methylation of the paroxetine-catechol metabolite to the corresponding guaiacol regioisomers in S-9 incubations. While the NADPH-dependent covalent binding was attenuated by GSH and SAM, these reagents did not alter paroxetine's ability to inactivate P 450 2D6, suggesting that the reactive intermediate responsible for P 450 inactivation did not leave the active site to react with other proteins. The results of the studies indicate that in addn. to the low once-a-day dosing regimen (20 mg) of paroxetine, efficient scavenging of the catechol and quinone metabolites by SAM and GSH, resp., serves as an explanation for the excellent safety record of paroxetine despite the fact that it undergoes bioactivation.
- 50(a) Daugan, A.; Grondin, P.; Ruault, C.; Le Monnier de Gouville, A.-C.; Coste, H.; Kirilovsky, J.; Hyafil, F.; Labaudiniere, R. The discovery of tadalafil: a novel and highly selective PDE5 Inhibitor. 1:5,6,11,11a-tetrahydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b]indole-1,3(2H)-dione analogues. J. Med. Chem. 2003, 46, 4525– 4532, DOI: 10.1021/jm030056e[ACS Full Text.], [CAS], Google Scholar50ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXnvVCju78%253D&md5=7c3b9aaf206cb18faaafc398c304357cThe discovery of tadalafil: a novel and highly selective PDE5 inhibitor. 1: 5,6,11,11a-tetrahydro-1H-imidazo[1',5':1,6]pyrido[3,4-b]indole-1,3(2H)-dione analoguesDaugan, Alain; Grondin, Pascal; Ruault, Cecile; Le Monnier de Gouville, Anne-Charlotte; Coste, Herve; Kirilovsky, Jorge; Hyafil, Francois; Labaudiniere, RichardJournal of Medicinal Chemistry (2003), 46 (21), 4525-4532CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Starting from Et β-carboline-3-carboxylate (β-CCE), 1, a modest inhibitor of type 5 phosphodiesterase (PDE5), a series of functionalized tetrahydro-β-carboline derivs. has been identified as a novel chem. class of potent and selective PDE5 inhibitors. Optimization of the side chain on the hydantoin ring of initial lead compd. 2 and of the arom. ring on position 5 led to the identification of compd. 6e, a highly potent and selective PDE5 inhibitor, with greater selectivity for PDE5 vs. PDE1-4 than sildenafil. Compd. 6e demonstrated a long lasting and significant blood pressure lowering effect after iv administration in the spontaneously hypertensive rat model but showed only moderate oral in vivo efficacy.(b) Daugan, A.; Grondin, P.; Ruault, C.; Le Monnier de Gouville, A. C.; Coste, H.; Linget, J. M.; Kirilovsky, J.; Hyafil, F.; Labaudinière, R. The discovery of tadalafil: a novel and highly selective PDE5 Inhibitor. 2:2,3,6,7,12,12a-hexahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione analogues. J. Med. Chem. 2003, 46, 4533– 4542, DOI: 10.1021/jm0300577[ACS Full Text.], [CAS], Google Scholar50bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXnvVCisrs%253D&md5=daaf79b5155dcea5b8c258fe7b05f436The discovery of tadalafil: a novel and highly selective PDE5 inhibitor. 2: 2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione analogueDaugan, Alain; Grondin, Pascal; Ruault, Cecile; Le Monnier de Gouville, Anne-Charlotte; Coste, Herve; Linget, Jean Michel; Kirilovsky, Jorge; Hyafil, Francois; Labaudiniere, RichardJournal of Medicinal Chemistry (2003), 46 (21), 4533-4542CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Modification of the hydantoin ring in the previously described lead compd. 2a has led to the discovery of compd. 12a, tadalafil, a highly potent and highly selective PDE5 inhibitor. The replacement of the hydantoin in compd. 2a by a piperazinedione ring led to compd. cis-11a which showed similar PDE5 inhibitory potency. Introduction of a 3,4-methylenedioxy substitution on the Ph ring in position 6 led to a potent PDE5 inhibitor cis-11c with increased cellular potency. Optimization of the chain on the piperazinedione ring led to the identification of the racemic cis-N-Me deriv. 11i. High diastereospecificity for PDE5 inhibition was obsd. in the piperazinedione series with the cis-(6R,12aR) enantiomer displaying the highest PDE5 inhibitory activity. The piperazinedione 12a, tadalafil (GF196960), has been identified as a highly potent PDE5 inhibitor (IC50 = 5 nM) with high selectivity for PDE5 vs. PDE1-4 and PDE6. Compd. 12a displays 85-fold greater selectivity vs. PDE6 than sildenafil 1. 12A showed profound and long-lasting blood pressure lowering activity (30 mmHg/>7 h) in the spontaneously hypertensive rat model after oral administration (5 mg/kg).(c) Curran, M. P.; Keating, G. M. Tadalafil. Drugs 2003, 63, 2203– 2212, DOI: 10.2165/00003495-200363200-00004[Crossref], [PubMed], [CAS], Google Scholar50chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXptFCis78%253D&md5=c749c366bbb1d7175bc4bb14ddd5cea5TadalafilCurran, Monique P.; Keating, Gillian M.Drugs (2003), 63 (20), 2203-2212CODEN: DRUGAY; ISSN:0012-6667. (Adis International Ltd.)A review. Tadalafil is a selective phosphodiesterase type 5 inhibitor that is effective in men with mild-to-severe erectile dysfunction (ED), including those with diabetes mellitus. The improvement in the erectile function domain score on the International Index of Erectile Function (IIEF) and the percentage of sexual intercourse attempts marked by successful vaginal penetration and completion was significantly greater with on-demand (not more than once daily) tadalafil 10 or 20mg than placebo in trials of 12 wk' duration. Improvement in scores on other domains of the IIEF and the percentage of pos. responses to a Global Assessment Question measuring erection improvement were also significantly greater with on-demand tadalafil than placebo. The adverse events assocd. with tadalafil were generally mild to moderate and decreased in frequency with continued administration. The most commonly reported adverse events were headache and dyspepsia. The incidence of cardiovascular adverse events was not significantly different in tadalafil or placebo recipients.
- 51Hartmann, J. T.; Lipp, H.-P. Camptothecin and podophyllotoxin derivatives inhibitors of topoisomerase I and II - mechanisms of action, pharmacokinetics and toxicity profile. Drug Saf. 2006, 29, 209– 230, DOI: 10.2165/00002018-200629030-00005[Crossref], [PubMed], [CAS], Google Scholar51https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XjslClsb8%253D&md5=96237fb19afbeb81954d01d06979733fCamptothecin and podophyllotoxin derivatives: inhibitors of topoisomerase I and II - mechanisms of action, pharmacokinetics and toxicity profileHartmann, Joerg T.; Lipp, Hans-PeterDrug Safety (2006), 29 (3), 209-230CODEN: DRSAEA; ISSN:0114-5916. (Adis International Ltd.)A review. Camptothecins represent an established class of effective agents that selectively target topoisomerase I by trapping the catalytic intermediate of the topoisomerase I-DNA reaction, the cleavage complex. The water-sol. salt camptothecin-sodium - introduced in early trials in the 1960s - was highly toxic in animals, whereas the semisynthetic derivs. irinotecan and topotecan did not cause hemorrhagic cystitis because of their higher physicochem. stability and soly. at lower pH values. Myelosuppression, neutropenia and, to a lesser extent, thrombocytopenia are dose-limiting toxic effects of topotecan. In contrast to the structurally-related topotecan, irinotecan is a prodrug which has to be converted to SN-38, its active form. SN-38 is inactivated by conjugation, thus patients with Gilbert's syndrome and other forms of genetic glucuronidation deficiency are at an increased risk of irinotecan-induced adverse effects, such as neutropenia and diarrhea. The cytotoxic mechanism of podophyllotoxin is the inhibition of topoisomerase II. Common adverse effects of etoposide include dose-limiting myelosuppression. Hypersensitivity reactions are more common with etoposide and teniposide than with etoposide phosphate because the formulations of the former contain sensitizing solubilizers. Leukopenia and thrombocytopenia occur in 65% and 80%, resp., of patients after administration of conventional doses of teniposide. Anorexia, vomiting and diarrhea are generally of mild severity after administration of conventional doses of topoisomerase II inhibitors. Clin. pharmacokinetic studies have revealed substantial interindividual variabilities regarding the area under the concn.-time curve values and steady-state concns. for all drugs reviewed in this article. Irinotecan, etoposide and teniposide are degraded via complex metabolic pathways. In contrast, topotecan primarily undergoes renal excretion. Regarding etoposide and teniposide, the extent of catechol formation over time during drug metab. may be assocd. with a higher risk for secondary malignancies.
- 52Murray, M. Mechanisms of inhibitory and regulatory effects of methylenedioxyphenyl compounds on cytochrome P450-dependent drug oxidation. Curr. Drug Metab. 2000, 1, 67– 84, DOI: 10.2174/1389200003339270[Crossref], [PubMed], [CAS], Google Scholar52https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXlt1Whurs%253D&md5=dcafc824c8bcd0080d256d6dd8c50ae7Mechanisms of inhibitory and regulatory effects of methylenedioxyphenyl compounds on cytochrome P450-dependent drug oxidationMurray, MichaelCurrent Drug Metabolism (2000), 1 (1), 67-84CODEN: CDMUBU ISSN:. (Bentham Science Publishers Ltd.)A review with 110 refs. Cytochrome P 450 (CYP) enzymes catalyze the oxidative conversion of drugs and other lipophilic compds. to hydrophilic metabolites. Thus, CYPs play a dominant role in the elimination of drugs from the body. Inhibitory interactions occur when drugs compete for oxidn. by specific CYPs, whereas certain drugs increase the capacity for oxidative biotransformation by inducing the synthesis of new CYPs. Methylenedioxyphenyl (MDP) compds. have been widely employed as com. important pesticide synergists and a no. of derivs. are found in oils and spices. MDP compds. are of considerable toxicol. significance because of their capacity to inhibit and induce CYP enzymes in mammals; some derivs. produce neurotoxic and hepatotoxic effects. Although there are relatively few therapeutic agents of present clin. importance that possess the MDP structural feature, the synthesis and preclin. evaluation of such agents appears to be increasing. In the context of the existing literature surrounding MDP compds. it is noteworthy that these potential drugs also elicit significant modulatory effects on CYP activities in rat and human liver. These developments indicate the importance of understanding the chem. mechanisms by which MDPs interact with CYPs. Thus, the presence of the MDP structure may undermine the potential clin. value of new drugs.
- 53Bardin, E.; Pastor, A.; Semeraro, M.; Golec, A.; Hayes, K.; Chevalier, B.; Berhal, F.; Prestat, G.; Hinzpeter, A.; Gravier-Pelletier, C.; Pranke, I.; Sermet-Gaudelus, I. Modulators of CFTR. Updates on clinical development and future directions. Eur. J. Med. Chem. 2021, 213, 113195, DOI: 10.1016/j.ejmech.2021.113195[Crossref], [PubMed], [CAS], Google Scholar53https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXjtVWisLs%253D&md5=347dc40d958b08ffae8e39271a78ca9cModulators of CFTR. Updates on clinical development and future directionsBardin, Emmanuelle; Pastor, Alexandra; Semeraro, Michaela; Golec, Anita; Hayes, Kate; Chevalier, Benoit; Berhal, Farouk; Prestat, Guillaume; Hinzpeter, Alexandre; Gravier-Pelletier, Christine; Pranke, Iwona; Sermet-Gaudelus, IsabelleEuropean Journal of Medicinal Chemistry (2021), 213 (), 113195CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)Cystic fibrosis (CF) is the most frequent life-limiting autosomal recessive disorder in the Caucasian population. It is due to mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Current symptomatic CF therapies, which treat the downstream consequences of CFTR mutations, have increased survival. Better knowledge of the CFTR protein has enabled pharmacol. therapy aiming to restore mutated CFTR expression and function. These CFTR "modulators" have revolutionised the CF therapeutic landscape, with the potential to transform prognosis for a considerable no. of patients. This review provides a brief summary of their mechanism of action and presents a thorough review of the results obtained from clin. trials of CFTR modulators.
- 54Keith, J. M.; Jones, W. M.; Tichenor, M.; Liu, J.; Seierstad, M.; Palmer, J. A.; Webb, M.; Karbarz, M.; Scott, B. P.; Wilson, S. J.; Luo, L.; Wennerholm, M. L.; Chang, L.; Rizzolio, M.; Rynberg, R.; Chaplan, S. R.; Breitenbucher, J. G. Preclinical characterization of the FAAH inhibitor JNJ-42165279. ACS Med. Chem. Lett. 2015, 6, 1204– 1208, DOI: 10.1021/acsmedchemlett.5b00353[ACS Full Text], [CAS], Google Scholar54https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhslGms73P&md5=fc681414ace29f39906fdd62c204114bPreclinical Characterization of the FAAH Inhibitor JNJ-42165279Keith, John M.; Jones, William M.; Tichenor, Mark; Liu, Jing; Seierstad, Mark; Palmer, James A.; Webb, Michael; Karbarz, Mark; Scott, Brian P.; Wilson, Sandy J.; Luo, Lin; Wennerholm, Michelle L.; Chang, Leon; Rizzolio, Michele; Rynberg, Raymond; Chaplan, Sandra R.; Breitenbucher, J. GuyACS Medicinal Chemistry Letters (2015), 6 (12), 1204-1208CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)The preclin. characterization of the aryl piperazinyl urea inhibitor of fatty acid amide hydrolase (FAAH) JNJ-42165279 I is described. JNJ-42165279 covalently inactivates the FAAH enzyme, but is highly selective with regard to other enzymes, ion channels, transporters, and receptors. JNJ-42165279 exhibited excellent ADME and pharmacodynamic properties as evidenced by its ability to block FAAH in the brain and periphery of rats and thereby cause an elevation of the concns. of anandamide (AEA), oleoyl ethanolamide (OEA), and palmitoyl ethanolamide (PEA). The compd. was also efficacious in the spinal nerve ligation (SNL) model of neuropathic pain. The combination of good phys., ADME, and PD properties of JNJ-42165279 supported it entering the clin. portfolio.
- 55Rose, W. C.; Marathe, P. H.; Jang, G. R.; Monticello, T. M.; Balasubramanian, B. N.; Long, B.; Fairchild, C. R.; Wall, M. E.; Wani, M. C. Novel fluoro-substituted camptothecins: in vivo antitumor activity, reduced gastrointestinal toxicity and pharmacokinetic characterization. Cancer Chemother. Pharmacol. 2006, 58, 73– 85, DOI: 10.1007/s00280-005-0128-y[Crossref], [PubMed], [CAS], Google Scholar55https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XjslGjsbg%253D&md5=97ecbd7d19b5e051255c5c0dc03b215aNovel fluoro-substituted camptothecins: in vivo antitumor activity, reduced gastrointestinal toxicity and pharmacokinetic characterizationRose, William C.; Marathe, Punit H.; Jang, Graham R.; Monticello, Thomas M.; Balasubramanian, Balu N.; Long, Byron; Fairchild, Craig R.; Wall, Monroe E.; Wani, Mansukh C.Cancer Chemotherapy and Pharmacology (2006), 58 (1), 73-85CODEN: CCPHDZ; ISSN:0344-5704. (Springer)Purpose: The novel fluoro-substituted camptothecin analog, BMS-286309, and its prodrug, BMS-422461, were evaluated for their pharmacol., toxicol., metabolic and pharmacokinetic developmental potential. Methods: In vitro and in vivo assays were used to assess the compds. for topoisomerase I activity, antitumor activity, gastrointestinal (GI) toxicity, and pharmacokinetic parameters. Results: BMS-286309-induced topoisomerase I-mediated DNA breaks in vitro and was similar in potency to camptothecin. Both BMS-286309 and -422461 were comparable to irinotecan regarding preclin. antitumor activity assessed in mice bearing distal site murine and human tumors. BMS-422461 was also found to be orally active. Both analogs were >100-fold more potent in vivo than irinotecan and both were superior to irinotecan with respect to toxicol. assessment of GI injury in mice. The generation of parent compd. from BMS-422461 was qual. similar in mouse, rat and human blood and liver S9 fractions. The percentage of BMS-286309 remaining as the active lactone form at equil. was comparable in mouse and human plasma. The pharmacokinetic profile in rat blood demonstrated that BMS-422461 was rapidly cleaved to BMS-286309. Conclusions: The favorable in vivo metabolic activation of BMS-422461, and the pharmacokinetic characteristics of BMS-286309, suggest that the good efficacy of BMS-422461 is derived from robust in vivo release of BMS-286309 in rodents and the likelihood that this biotransformation will be preserved in humans. The comparable antitumor activity of BMS-422461 to irinotecan, as well as reduced preclin. GI toxicity, make this novel camptothecin analog attractive for clin. development.
- 56Alig, L.; Alsenz, J.; Andjelkovic, M.; Bendels, S.; Bénardeau, A.; Bleicher, K.; Bourson, A.; David-Pierson, P.; Guba, W.; Hildbrand, S.; Kube, D.; Lübbers, T.; Mayweg, A. V.; Narquizian, R.; Neidhart, W.; Nettekoven, M.; Plancher, J.; Rocha, C.; Rogers-Evans, M.; Röver, S.; Schneider, G.; Taylor, S.; Waldmeier, P. Benzodioxoles: novel cannabinoid-1 receptor inverse agonists for the treatment of obesity. J. Med. Chem. 2008, 51, 2115– 2127, DOI: 10.1021/jm701487t[ACS Full Text], [CAS], Google Scholar56https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXjt1Wqsbg%253D&md5=ac2fb302fb7c3a7cf6c46994d87bd83aBenzodioxoles: Novel Cannabinoid-1 Receptor Inverse Agonists for the Treatment of ObesityAlig, Leo; Alsenz, Jochem; Andjelkovic, Mirjana; Bendels, Stefanie; Benardeau, Agnes; Bleicher, Konrad; Bourson, Anne; David-Pierson, Pascale; Guba, Wolfgang; Hildbrand, Stefan; Kube, Dagmar; Luebbers, Thomas; Mayweg, Alexander V.; Narquizian, Robert; Neidhart, Werner; Nettekoven, Matthias; Plancher, Jean-Marc; Rocha, Cynthia; Rogers-Evans, Mark; Roever, Stephan; Schneider, Gisbert; Taylor, Sven; Waldmeier, PiusJournal of Medicinal Chemistry (2008), 51 (7), 2115-2127CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The application of the evolutionary fragment-based de novo design tool TOPol. Assigning System (TOPAS), starting from a known CB1R (CB-1 receptor) ligand, followed by further refinement principles, including pharmacophore compliance, chem. tractability, and drug likeness, allowed the identification of benzodioxoles as a novel CB1R inverse agonist series. Extensive multidimensional optimization was rewarded by the identification of promising lead compds., showing in vivo activity. These compds. reversed the CP-55940-induced hypothermia in Naval Medical Research Institute (NMRI) mice and reduced body-wt. gain, as well as fat mass, in diet-induced obese Sprague-Dawley rats. Herein, we disclose the tools and strategies that were employed for rapid hit identification, synthesis and generation of structure-activity relationships, ultimately leading to the identification of (+)-[(R)-2-(2,4-dichloride-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone (I). Biochem., pharmacokinetic, and pharmacodynamic characteristics of I are discussed.
- 57(a) Boyle, C. D.; Chackalamannil, S.; Chen, L.; Dugar, S.; Pushpavanam, P.; Billard, W.; Binch, H.; Crosby, H.; Cohen-Williams, M.; Coffin, V. L.; Duffy, R. A.; Ruperto, V.; Lachowicz, J. E. Benzylidene ketal derivatives as M2 muscarinic receptor antagonists. Bioorg. Med. Chem. Lett. 2000, 10, 2727– 2730, DOI: 10.1016/S0960-894X(00)00553-9[Crossref], [PubMed], [CAS], Google Scholar.57ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXosFelsbk%253D&md5=c5a5fc7ae27902089c099213328b5e18Benzylidene ketal derivatives as M2 muscarinic receptor antagonistsBoyle, C. D.; Chackalamannil, S.; Chen, L.-Y.; Dugar, S.; Pushpavanam, P.; Billard, W.; Binch, H.; Crosby, G.; Cohen-Williams, M.; Coffin, V. L.; Duffy, R. A.; Ruperto, V.; Lachowicz, J. E.Bioorganic & Medicinal Chemistry Letters (2000), 10 (24), 2727-2730CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)Benzylidene ketal derivs. were investigated as selective M2 receptor antagonists for the treatment of Alzheimer's disease. Compd. I was discovered to have subnanomolar M2 receptor affinity and 100-fold selectivity against other muscarinic receptors. Also, I demonstrated in vivo efficacy in rodent models of muscarinic activity and cognition.(b) Boyle, C. D.; Chackalamannil, S.; Clader, J. W.; Greenlee, W. J.; Josien, H. B.; Kaminski, J. J.; Kozlowski, J. A.; McCombie, S. W.; Nazareno, D. V.; Tagat, J. R.; Wang, Y.; Zhou, G.; Billard, W.; Binch, H.; Crosby, G.; Cohen-Williams, M.; Coffin, V. L.; Cox, K. A.; Grotz, D. E.; Duffy, R. A.; Ruperto, V.; Lachowicz, J. E. Metabolic stabilization of benzylidene ketal M2 muscarinic receptor antagonists via halonaphthoic acid substitution. Bioorg. Med. Chem. Lett. 2001, 11, 2311– 2314, DOI: 10.1016/S0960-894X(01)00435-8[Crossref], [PubMed], [CAS], Google Scholar57bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXmt1yqu70%253D&md5=0232ced3ab4512f9be66a3b36a4adb8dMetabolic stabilization of benzylidene ketal M2 muscarinic receptor antagonists via halonaphthoic acid substitutionBoyle, C. D.; Chackalamannil, S.; Clader, J. W.; Greenlee, W. J.; Josien, H. B.; Kaminski, J. J.; Kozlowski, J. A.; McCombie, S. W.; Nazareno, D. V.; Tagat, J. R.; Wang, Y.; Zhou, G.; Billard, W.; Binch, H.; Crosby, G.; Cohen-Williams, M.; Coffin, V. L.; Cox, K. A.; Grotz, D. E.; Duffy, R. A.; Ruperto, V.; Lachowicz, J. E.Bioorganic & Medicinal Chemistry Letters (2001), 11 (17), 2311-2314CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)The potential toxicol. liabilities of a previously studied M2 muscarinic antagonist benzylidene ketal were addressed by replacing the methylenedioxyphenyl moiety with a p-methoxyphenyl group, resulting in M2 selective compds. such as (I). Several halogenated naphthamide derivs. of I were studied to improve the pharmacokinetic profile via blockage of oxidative metab. Compd. (II) demonstrated excellent M2 affinity and selectivity, human microsomal stability, and oral bioavailability in rodents and primates.
- 58(a) Franchini, S.; Sorbi, C.; Linciano, P.; Carnevale, G.; Tait, A.; Ronsisvalle, S.; Buccioni, M.; Del Bello, F.; Cilia, A.; Pirona, L.; Denora, N.; Iacobazzi, R. M.; Brasili, L. 1,3-Dioxane as a scaffold for potent and selective 5-HT1AR agonist with in-vivo anxiolytic, anti-depressant and anti-nociceptive activity. Eur. J. Med. Chem. 2019, 176, 310– 325, DOI: 10.1016/j.ejmech.2019.05.024[Crossref], [PubMed], [CAS], Google Scholar.58ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXpvFeis7o%253D&md5=c5601fb67fe50e79223f254f141097701,3-Dioxane as a scaffold for potent and selective 5-HT1AR agonist with in-vivo anxiolytic, anti-depressant and anti-nociceptive activityFranchini, Silvia; Sorbi, Claudia; Linciano, Pasquale; Carnevale, Gianluca; Tait, Annalisa; Ronsisvalle, Simone; Buccioni, Michela; Del Bello, Fabio; Cilia, Antonio; Pirona, Lorenza; Denora, Nunzio; Iacobazzi, Rosa Maria; Brasili, LivioEuropean Journal of Medicinal Chemistry (2019), 176 (), 310-325CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)A series of compds. generated by ring expansion/opening and mol. elongation/simplification of the 1,3-dioxolane scaffold were prepd. and tested for binding affinity at 5-HT1AR and α1 adrenoceptors. The compds. with greater affinity were selected for further functional studies. N-((2,2-diphenyl-1,3-dioxan-5-yl)methyl)-2-(2-methoxyphenoxy)ethan-1-ammonium hydrogen oxalate I emerged as highly potent full agonist at the 5-HT1AR (pKi 5-HT1A = 8.8; pD2 = 9.22, %Emax = 92). The pharmacokinetic data in rats showed that the orally administered I has a high biodistribution in the brain compartment. Thus, I was further investigated in-vivo, showing an anxiolytic and antidepressant effect. Moreover, in the formalin test, the above compd. was able to decrease the late response to the noxious stimulus, indicating a potential use in the treatment of chronic pain.(b) Linciano, P.; Sorbi, C.; Comitato, A.; Lesniak, A.; Bujalska-Zadrożny, M.; Pawłowska, A.; Bielenica, A.; Orzelska-Górka, J.; Kedzierska, E.; Biała, G.; Ronsisvalle, S.; Limoncella, S.; Casarini, L.; Cichero, E.; Fossa, P.; Satała, G.; Bojarski, A. J.; Brasili, L.; Bardoni, R.; Franchini, S. Identification of a potent and selective 5-HT1A receptor agonist with in vitro and in vivo antinociceptive activity. ACS Chem. Neurosci. 2020, 11, 4111– 4127, DOI: 10.1021/acschemneuro.0c00289[ACS Full Text], [CAS], Google Scholar58bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXisVCksb3O&md5=fa1038f2e60e9a0fe307c46316427a36Identification of a Potent and Selective 5-HT1A Receptor Agonist with In Vitro and In Vivo Antinociceptive ActivityLinciano, Pasquale; Sorbi, Claudia; Comitato, Antonella; Lesniak, Anna; Bujalska-Zadrozny, Magdalena; Pawlowska, Agata; Bielenica, Anna; Orzelska-Gorka, Jolanta; Kedzierska, Ewa; Biala, Grazyna; Ronsisvalle, Simone; Limoncella, Silvia; Casarini, Livio; Cichero, Elena; Fossa, Paola; Satala, Grzegorz; Bojarski, Andrzej J.; Brasili, Livio; Bardoni, Rita; Franchini, SilviaACS Chemical Neuroscience (2020), 11 (24), 4111-4127CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)Opioids are the gold std. drugs for the treatment of acute and chronic severe pain, although their serious side effects constitute a big limitation. In the search for new and safer drugs, 5-HT1AR agonists are emerging as potential candidates in pain relief therapy. In this work, we evaluated the affinity and activity of enantiomers of the two newly synthesized, potent 5-HT1AR agonists N-[(2,2-diphenyl-1,3-dioxolan-4-yl)methyl]-2-[2-(pyridin-4-yl)phenoxy]ethan-1-ammonium hydrogenoxalate (rac-1) and N-((2,2-diphenyl-1,3-dioxolan-4-yl)methyl)-2-(2-(1-methyl-1H-imidazol-5-yl)phenoxy)ethan-1-ammonium hydrogenoxalate (rac-2) in vitro and in vivo. The role of chirality in the interaction with 5-HT1AR was evaluated by mol. docking. The activity of the rac-1 was tested in mouse models of acute pain (hot plate) and severe tonic nociceptive stimulation (intraplantar formalin test). Rac-1 was active in the formalin test with a redn. in paw licking in both phases at 10 mg/kg, and its effect was abolished by the selective 5-HT1AR antagonist, WAY-100635. The eutomer (S)-1, but not the racemate, was active during the hot plate test at 10 and 20 mg/kg, and this effect was abolished by 30 min treatment with WAY-100635 at 30 min. Similarly to 8-OH-DPAT, (S)-1 evoked a slow outward current and depressed spontaneous glutamatergic transmission in superficial dorsal horn neurons, more effectively than rac-1. The eutomer (S)-1 showed promising developability properties, such as high selectivity over 5-HT subtypes, no interaction with the μ receptors, and low hepato- and cardiotoxicity. Therefore, (S)-1 may represent a potential candidate for the treatment of acute and chronic pain without having the adverse effects that are commonly assocd. with the classic opioid drugs.
- 59(a) Dunn, M. I. A new antihypertensive drug. JAMA, J. Am. Med. Assoc. 1981, 245, 1639– 1642, DOI: 10.1001/jama.245.16.1639[Crossref], [PubMed], [CAS], Google Scholar.59ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL3M7ksFKlsA%253D%253D&md5=afad866489d11a33f161808499465c14Guanadrel. A new antihypertensive drugDunn M I; Dunlap J LJAMA (1981), 245 (16), 1639-42 ISSN:0098-7484.Guanadrel sulfate, a new adrenergic neuron inhibitor similar to guanethidine sulfate, was tested on 199 outpatients by 11 investigators. The patients had mild, moderate, or severe hypertension as determined by diastolic blood pressures of 95 to 105, 106 to 114, and 115 to 120 mm Hg, respectively. Guanadrel was found to be an effective antihypertensive agent for all levels of hypertension. Since guanadrel has a short onset of action and a short offset of action, which prevents many of the side effects of guanathidine, the dosage could be adjusted rapidly and safely. At low doses side effects are infrequent. There was no organ toxicity and no CNS effect. Guanadrel should be an effective step II or step III drug for treatment of hypertension.(b) Hengstmann, J. H.; Falkner, F. C. Disposition of guanethidine during chronic oral therapy. Eur. J. Clin. Pharmacol. 1979, 15, 121– 125, DOI: 10.1007/BF00609875[Crossref], [PubMed], [CAS], Google Scholar.59bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaE1M7mvFCgsA%253D%253D&md5=fc3e3bd45a46c971db3ab8b704d3510eDisposition of guanethidine during chronic oral therapyHengstmann J H; Falkner F CEuropean journal of clinical pharmacology (1979), 15 (2), 121-5 ISSN:0031-6970.The plasma level and urinary excretion rate of guanethidine have been measured in 30 patients during oral maintenance therapy, and in 5 patients following discontinuous of therapy. A significant correlation was found between the daily average urinary excretion and the maintenance dose, although wide interindividual variation was noted among patients maintained on the same dose. A statistically significant correlation was also observed between the area under the plasma level curve during the dose interval and the oral maintenance dose. After discontinuation of chronic therapy, the half-life of 1.5 days of the initial phase of elimination was essentially in agreement with the half-life of almost 2 days determined in acute studies. In addition, a second phase of elimination with a half-life of 4 to 8 days was observed.(c) Finnerty, F. A., Jr.; Brogden, R. N. Guanadrel, A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in hypertension. Drugs 1985, 30, 22– 31, DOI: 10.2165/00003495-198530010-00003[Crossref], [PubMed], [CAS], Google Scholar59chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL2M3osVKntQ%253D%253D&md5=415c04855c3f572afdb3c4ed0292ee11Guanadrel. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in hypertensionFinnerty F A Jr; Brogden R NDrugs (1985), 30 (1), 22-31 ISSN:0012-6667.Guanadrel sulphate is an orally active peripheral sympathetic inhibitor (adrenergic neuron-blocking drug). In comparative studies, guanadrel was comparable in efficacy with guanethidine or methyldopa in mild to moderately severe hypertension, although generally it caused fewer central nervous system side effects than methyldopa and less orthostatic dizziness and diarrhoea than guanethidine. However, its efficacy in patients whose blood pressure remains inadequately controlled by other drugs (except diuretics alone) has yet to be adequately demonstrated. Guanadrel has a rapid onset of action and a half-life of about 10 hours, thus dose titration can be achieved more rapidly than with guanethidine, and twice daily administration is appropriate. Generally, guanadrel has been well tolerated, withdrawal of treatment due to adverse effects seldom being necessary. Thus, guanadrel appears to be a suitable alternative to methyldopa for the treatment of mild to moderately severe hypertension not controlled adequately by diuretics alone.
- 60(a) Satoh, E.; Kasahara, R.; Fukatsu, K.; Aoki, T.; Harayama, H.; Murata, T. Benzpyrimoxan: design, synthesis, and biological activity of a novel insecticide. J. Pestic. Sci. 2021, 46, 109– 114, DOI: 10.1584/jpestics.D20-069[Crossref], [PubMed], [CAS], Google Scholar.60ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhsVCjtLnE&md5=7ca20d0eefd2aa85f45963e2c1f55b06Benzpyrimoxan: design, synthesis, and biological activity of a novel insecticideSatoh, Eikoh; Kasahara, Ryota; Fukatsu, Kosuke; Aoki, Takao; Harayama, Hiroto; Murata, TetsuyaJournal of Pesticide Science (Tokyo, Japan) (2021), 46 (1), 109-114CODEN: JPSTCF; ISSN:1349-0923. (Pesticide Science Society of Japan)Benzpyrimoxan (5-(1,3-dioxan-2-yl)-4-{[4-(trifluoromethyl)phenyl]methoxy}pyrimidine, NNI-1501) was discovered as a novel insecticide structurally characterized by a pyrimidine deriv. substituted with 1,3-dioxanyl and 4-trifluoromethylbenzyloxy groups. The compd. showed remarkable activity against nymphs of rice planthoppers, including strains resistant to existing insecticides. Furthermore, benzpyrimoxan had low adverse effects on pollinators and beneficial arthropods. Because of these features, benzpyrimoxan is expected to be a suitable part of an integrated pest management strategy. In this report, the history of the discovery to reach benzpyrimoxan and details of the structure-activity relationships are described.(b) Umetsu, N.; Shirai, Y. Development of novel pesticides in the 21st century. J. Pestic. Sci. 2020, 45, 54– 74, DOI: 10.1584/jpestics.D20-201[Crossref], [PubMed], [CAS], Google Scholar60bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXit1Knu7vE&md5=fb35005da013ff4d48214812839f4752Development of novel pesticides in the 21st centuryUmetsu, Noriharu; Shirai, YuichiJournal of Pesticide Science (Tokyo, Japan) (2020), 45 (2), 54-74CODEN: JPSTCF; ISSN:1349-0923. (Pesticide Science Society of Japan)A review. General trends and strategies for novel pesticides are summarized. Global pesticide sales and pesticide discovery research are also briefly ed. At least 105 chem. pesticides have been launched during the past decade or are under development: 43 fungicides, 34 insecticides/acaricides, 6 nematicides, 21 herbicides, and 1 herbicide safener. Most of them are safe to humans and environmentally friendly. The most developed fungicides are SDHI (succinate dehydrogenase inhibitors), DMI (demethylation inhibitors), QoI (quinone outside inhibitors), and QiI (quinone inside inhibitors). Due to the development of resistance to fungicides with existing modes of action, many fungicides possessing various novel modes of action have been launched or are under development. The trend of insecticide development is changing from organophosphorus, carbamate, and synthetic pyrethroids to nicotinic and diamide insecticides. During the past decade, compds. possessing a variety of novel modes of action have also been launched or are under development. Flupyradifurone and flupyrimin, exhibiting extremely low honeybee toxicity, have been developed and subjected to practical use. Herbicides possessing varied modes of action, such as acetolactate synthase, p-hydroxyphenylpyruvate dioxygenase, protoporphyrinogen oxidase, and very-long-chain fatty acid elongase.
- 61(a) McAtee, L. C.; Sutton, S. W.; Rudolph, D. A.; Li, X.; Aluisio, L. E.; Phuong, V. K.; Dvorak, C. A.; Lovenberg, T. W.; Carruthers, N. I.; Jones, T. K. Novel substituted 4-phenyl-[1,3]dioxanes: potent and selective orexin receptor 2 (OX2R) antagonists. Bioorg. Med. Chem. Lett. 2004, 14, 4225– 4229, DOI: 10.1016/j.bmcl.2004.06.032[Crossref], [PubMed], [CAS], Google Scholar.61ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXlvVWjsbg%253D&md5=fe754c8f27a856d307d1e27caf3f6806Novel substituted 4-phenyl-[1,3]dioxanes: potent and selective orexin receptor 2 (OX2R) antagonistsMcAtee, Laura C.; Sutton, Steven W.; Rudolph, Dale A.; Li, Xiaobing; Aluisio, Leah E.; Phuong, Victor K.; Dvorak, Curt A.; Lovenberg, Timothy W.; Carruthers, Nicholas I.; Jones, Todd K.Bioorganic & Medicinal Chemistry Letters (2004), 14 (16), 4225-4229CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science B.V.)Orexins, also termed hypocretins, consist of two neuropeptide agonists (orexin A and B) interacting with two known G-protein coupled receptors (OX1R and OX2R). In addn. to other biol. functions, the orexin-2 receptor is thought to be an important modulator of sleep and wakefulness. Herein we describe a series of novel, selective OX2R antagonists consisting of substituted 4-phenyl-[1,3]dioxanes. One such antagonist is 1-(2,4-dibromo-phenyl)-3-((4S,5S)-2,2-dimethyl-4-phenyl-[1,3]dioxan-5-yl)-urea (I), which is bound by the OX2R with a pKi of 8.3, has a pKb of 7.9, and is 600-fold selective for the OX2R over the OX1R.(b) Letavic, M. A.; Bonaventure, P.; Carruthers, N. I.; Dugovic, C.; Koudriakova, T.; Lord, B.; Lovenberg, T. W.; Ly, K. S.; Mani, N. S.; Nepomuceno, D.; Pippel, D. J.; Rizzolio, M.; Shelton, J. E.; Shah, C. R.; Shireman, B. T.; Young, L. K.; Yun, S. Novel octahydropyrrolo[3,4-c]pyrroles are selective orexin-2 antagonists: SAR leading to a clinical candidate. J. Med. Chem. 2015, 58, 5620– 5636, DOI: 10.1021/acs.jmedchem.5b00742[ACS Full Text], [CAS], Google Scholar61bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVansL%252FP&md5=6d8785a362aab57c84f6a6db0775d84eNovel Octahydropyrrolo[3,4-c]pyrroles Are Selective Orexin-2 Antagonists: SAR Leading to a Clinical CandidateLetavic, Michael A.; Bonaventure, Pascal; Carruthers, Nicholas I.; Dugovic, Christine; Koudriakova, Tatiana; Lord, Brian; Lovenberg, Timothy W.; Ly, Kiev S.; Mani, Neelakandha S.; Nepomuceno, Diane; Pippel, Daniel J.; Rizzolio, Michele; Shelton, Jonathan E.; Shah, Chandra R.; Shireman, Brock T.; Young, Lana K.; Yun, SujinJournal of Medicinal Chemistry (2015), 58 (14), 5620-5636CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The preclin. characterization of novel octahydropyrrolo[3,4-c]pyrroles that are potent and selective orexin-2 antagonists is described. Optimization of physicochem. and DMPK properties led to the discovery of compds. with tissue distribution and duration of action suitable for evaluation in the treatment of primary insomnia. These selective orexin-2 antagonists are proven to promote sleep in rats, and this work ultimately led to the identification of a compd. that progressed into human clin. trials for the treatment of primary insomnia. The synthesis, SAR, and optimization of the pharmacokinetic properties of this series of compds. as well as the identification of the clin. candidate I are described herein.
- 62(a) Trabocchi, A.; Menchi, G.; Guarna, F.; Machetti, F.; Scarpi, D.; Guarna, A. Design, synthesis, and applications of 3-aza-6,8-dioxabicyclo[3.2.1]octane-based scaffolds for peptidomimetic chemistry. Synlett 2006, 2006, 0331– 0353, DOI: 10.1055/s-2006-926249 .(b) Trabocchi, A.; Cini, N.; Menchi, G.; Guarna, A. A new bicyclic proline-mimetic amino acid. Tetrahedron Lett. 2003, 44, 3489– 3492, DOI: 10.1016/S0040-4039(03)00663-4[Crossref], [CAS], Google Scholar.62bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXislejurc%253D&md5=384064db208f320f0afa5df534e84949A new bicyclic proline-mimetic amino acidTrabocchi, Andrea; Cini, Nicoletta; Menchi, Gloria; Guarna, AntonioTetrahedron Letters (2003), 44 (17), 3489-3492CODEN: TELEAY; ISSN:0040-4039. (Elsevier Science Ltd.)Constrained bicyclic α-amino acids I-IV as proline-mimetics were synthesized. For example, I and II were synthesized in several steps from D-α,β-isopropylidene-glycerol triflate and O-protected L- or D-serinol derivs. H2NCH(CH2OR)CH2OH (R = SiMe2Bu-t, CH2Ph), thus allowing the prepn. of either D- or L-proline mimetics. Similarly, III and IV were prepd. from L-α,β-isopropylidene-glycerol triflate. I-IV were prepd. as N-Fmoc-amino acid suitable for solid-phase peptide synthesis.(c) Trabocchi, A.; Menchi, G.; Danieli, E.; Guarna, A. Synthesis of a bicyclic δ-amino acid as a constrained Gly-Asn dipeptide isostere. Amino Acids 2008, 35, 37– 44, DOI: 10.1007/s00726-007-0636-7[Crossref], [PubMed], [CAS], Google Scholar.62chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXmslWjt7w%253D&md5=b60bf533ab4a13275eefd2ce9f34e0ccSynthesis of a bicyclic δ-amino acid as a constrained Gly-Asn dipeptide isostereTrabocchi, A.; Menchi, G.; Danieli, E.; Guarna, A.Amino Acids (2008), 35 (1), 37-44CODEN: AACIE6; ISSN:0939-4451. (Springer Wien)δ-Amino acids are very attractive in drug discovery, esp. in the peptidomimetic area, because of their capability to act as dipeptide isosteres and reverse turn mimetics. Herein, the authors report the synthesis of a rigid δ-amino acid constrained by a 3-aza-6,8-dioxabicyclo[3.2.1]octane-based scaffold, which can be considered as a Gly-Asn dipeptide mimetic. Key steps are the condensation of glycidol and tartaric acid derivs., and the intramol. trans-acetalization of the oxidized adduct to give the bicyclic δ-amino acid. For example, L-tartaric acid deriv. as a starting material afforded the Gly-D-Asn isostere, and similarly, the enantiomeric D-tartaric acid deriv. provided the corresponding Gly-D-Asn isostere.(d) Machetti, F.; Bucelli, I.; Indiani, G.; Guarna, A. Neat reaction of carboxylic acid methyl esters and amines for efficient parallel synthesis of scaffold amide libraries. C. R. Chim. 2003, 6, 631– 633, DOI: 10.1016/S1631-0748(03)00097-3[Crossref], [CAS], Google Scholar.62dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXmvV2lu7g%253D&md5=62eab404e0791d43468f2844c1873690Neat reaction of carboxylic acid methyl esters and amines for efficient parallel synthesis of scaffold amide librariesMachetti, Fabrizio; Bucelli, Ilaria; Indiani, Giovanni; Guarna, AntonioComptes Rendus Chimie (2003), 6 (5-6), 631-633CODEN: CRCOCR; ISSN:1631-0748. (Editions Scientifiques et Medicales Elsevier)Efficient synthesis of unsubstituted and substituted amides is described. The reaction is characterized by its mildness and ease of work-up. A library of amides, was prepd. by heating esters I [X = O, S] with various amines.(e) Cini, N.; Danieli, E.; Menchi, G.; Trabocchi, A.; Bottoncetti, A.; Raspanti, S.; Pupi, A.; Guarna, A. 3-Aza-6,8-dioxabicyclo[3.2.1]octanes as new enantiopure heteroatom-rich tropane-like ligands of human dopamine transporter. Bioorg. Med. Chem. 2006, 14, 5110– 5120, DOI: 10.1016/j.bmc.2006.04.019[Crossref], [PubMed], [CAS], Google Scholar62ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XlvFyrt7o%253D&md5=a385832e3ddf35b45d74f02cde14ff303-Aza-6,8-dioxabicyclo[3.2.1]octanes as new enantiopure heteroatom-rich tropane-like ligands of human dopamine transporterCini, Nicoletta; Danieli, Elisa; Menchi, Gloria; Trabocchi, Andrea; Bottoncetti, Anna; Raspanti, Silvia; Pupi, Alberto; Guarna, AntonioBioorganic & Medicinal Chemistry (2006), 14 (15), 5110-5120CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)CNS diseases such as Parkinson, schizophrenia, and attention deficit hyperactivity disorder (ADHD) are characterized by a significant alteration of dopamine transporter (DAT) d. Thus, the development of compds. that are able to selectively interact with DAT is of great interest. Herein we describe the design and synthesis of a new set of 3-aza-6,8-dioxabicyclo[3.2.1]octanes having a tropane-like structure with addnl. heteroatoms at positions 3 and 6. The compds. were evaluated for their in vitro receptor binding properties toward human dopamine (hDAT) and serotonin (hSERT) transporters using [3H]WIN35,428 and [3H]citalopram as specific radioligands, resp. Biol. assays revealed that some compds. having the N-3 atom substituted with aryl groups possess significant affinity and selectivity for monoamine transporters, and in particular, compd. 5d displayed an IC50 of 21 nM toward DAT, and a good selectivity toward SERT (IC50 = 1042 nM). These results suggest that 3-aryl-3-aza-6,8-dioxabicyclo[3.2.1]octanes may represent a new class of DAT ligands.
- 63(a) Sherwood, J.; De bruyn, M.; Constantinou, A.; Moity, L.; McElroy, C. R.; Farmer, T. J.; Duncan, T.; Raverty, W.; Hunt, A. J.; Clark, J. H. Dihydrolevoglucosenone (Cyrene) as a bio-based alternative for dipolar aprotic solvents. Chem. Commun. 2014, 50, 9650– 9652, DOI: 10.1039/C4CC04133J[Crossref], [PubMed], [CAS], Google Scholar.63ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtVOnurnO&md5=4159e1a7d7eab47f2d05e686358dbe62Dihydrolevoglucosenone (Cyrene) as a bio-based alternative for dipolar aprotic solventsSherwood, James; De Bruyn, Mario; Constantinou, Andri; Moity, Laurianne; McElroy, C. Rob; Farmer, Thomas J.; Duncan, Tony; Raverty, Warwick; Hunt, Andrew J.; Clark, James H.Chemical Communications (Cambridge, United Kingdom) (2014), 50 (68), 9650-9652CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)Dihydrolevoglucosenone (Cyrene) is a bio-based mol., derived in two simple steps from cellulose, which demonstrates significant promise as a dipolar aprotic solvent. The dipolarity of dihydrolevoglucosenone is similar to NMP, DMF and sulfolane. Dihydrolevoglucosenone demonstrates similar performance to NMP in a fluorination reaction and the Menschutkin reaction.(b) Hughes, L.; McElroy, C. R.; Whitwood, A. C.; Hunt, A. J. Development of pharmaceutically relevant biobased intermediates though aldol condensation and Claisen-Schmidt reactions of dihydrolevoglucosenone (Cyrene®). Green Chem. 2018, 20, 4423– 4427, DOI: 10.1039/C8GC01227J[Crossref], [CAS], Google Scholar.63bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtVeisbjL&md5=e703ec22ec55663a5e18b062d7d81aecDevelopment of pharmaceutically relevant bio-based intermediates though aldol condensation and Claisen-Schmidt reactions of dihydrolevoglucosenone (Cyrene)Hughes, Liam; McElroy, Con R.; Whitwood, Adrian C.; Hunt, Andrew J.Green Chemistry (2018), 20 (19), 4423-4427CODEN: GRCHFJ; ISSN:1463-9262. (Royal Society of Chemistry)Dihydrolevoglucosenone (Cyrene) has been successfully utilized as a bio-based platform mol. for the synthesis of pharmaceutically relevant intermediates through aldol condensation reactions. Utilizing sustainable synthetic methodologies, the self-aldol condensation reaction of Cyrene was achieved in high purity, with isolated yields of 81.3%. Claisen-Schmidt reactions with a range of arom. and heteroarom. aldehydes yielded several previously unreported Cyrene-based compds., characterized by single-crystal X-ray diffraction, FT-IR, NMR and MS.(c) Liu, X.; Carr, P.; Gardiner, M. G.; Banwell, M. G.; Elbanna, A. H.; Khalil, Z. G.; Capon, R. J. Levoglucosenone and its pseudoenantiomer iso-levoglucosenone as scaffolds for drug discovery and development. ACS Omega 2020, 5, 13926– 13939, DOI: 10.1021/acsomega.0c01331[ACS Full Text], [CAS], Google Scholar63chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtVyrt7nM&md5=146e93da113016acdb9ce2d6966d6bb2Levoglucosenone and Its Pseudo-enantiomer iso-Levoglucosenone as Scaffolds for Drug Discovery and DevelopmentLiu, Xin; Carr, Paul; Gardiner, Michael G.; Banwell, Martin G.; Elbanna, Ahmed H.; Khalil, Zeinab G.; Capon, Robert J.ACS Omega (2020), 5 (23), 13926-13939CODEN: ACSODF; ISSN:2470-1343. (American Chemical Society)The bio-derived platform mol. levoglucosenone (LGO) and its readily prepd. pseudo-enantiomer (iso-LGO) have each been subjected to α-iodination reactions with the product halides then being engaged in palladium-catalyzed Ullmann cross-coupling reactions with various bromonitropyridines. The corresponding α-pyridinylated derivs., e.g. I, are produced as a result. Biol. screening of such products reveals that certain of them display potent and selective antimicrobial and/or cytotoxic properties. In contrast, the aza-indoles obtained by reductive cyclization of compds. such as 11 and 12 are essentially inactive in these respects. Preliminary mode-of-action studies are reported.
- 64(a) Sensi, P. History of the development of rifampin. Clin. Infect. Dis. 1983, 5, S402– S406, DOI: 10.1093/clinids/5.Supplement_3.S402 .(b) Wehrli, W.; Staehelin, M. Rifamycins and other ansamycins. Mechanism of Action of Antimicrobial and Antitumor Agents. Antibiotics. 1975, 3, 252– 268, DOI: 10.1007/978-3-642-46304-4_16
- 65(a) Oppolzer, W.; Prelog, V.; Sensi, P. The composition of rifamycin B and related rifamycins. Experientia 1964, 20, 336– 339, DOI: 10.1007/BF02171084[Crossref], [PubMed], [CAS], Google Scholar.65ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF2cXkvVCitbY%253D&md5=713bd4fd9add1713aad3c73a9aecc4a3Structure of rifomycin B and related rifomycinsOppolzer, W.; Prelog, V.; Sensi, P.Experientia (1964), 20 (6), 336-9CODEN: EXPEAM; ISSN:0014-4754.Structure I is proposed for rifomycin B, based on nuclear magnetic resonance, infrared, ultraviolet spectra, and chem. data for I and derived compds.(b) Leitich, J.; Oppolzer, W.; Prelog, V. On the configuration of rifamycin B and related rifamycins. Experientia 1964, 20, 343– 344, DOI: 10.1007/BF02171086[Crossref], [PubMed], [CAS], Google Scholar65bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF2cXkvFWqsLY%253D&md5=2d134d53f92202a2244923820c3d4150Configuration of rifamycin B and related rifamycinsLeitich, J.; Oppolzer, W.; Prelog, V.Experientia (1964), 20 (6), 343-4CODEN: EXPEAM; ISSN:0014-4754.The relative configurations of rifamycin B (I) and related rifamycins have been detd. by x-ray analysis, which gives information also about the relative configuration of the 9 asym. C-atoms (C12 and C20 to C27) and in part by nuclear magnetic resonance spectroscopy. The abs. configuration has been derived from the configuration of a degradation product, the dextrorotatory α,α'-dimethyl-pimelic acid, and was recognized as S-configuration.
- 66Bacchi, A.; Pelizzi, G.; Nebuloni, M.; Ferrari, P. Comprehensive study on structure-activity relationships of rifamycins: discussion of molecular and crystal structure and spectroscopic and thermochemical properties of rifamycin O. J. Med. Chem. 1998, 41, 2319– 2332, DOI: 10.1021/jm970791o[ACS Full Text], [CAS], Google Scholar66https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXjtlygtrk%253D&md5=a00455a0e5b2806d198df44f66f28761Comprehensive study on structure-activity relationship of rifamycins: discussion of molecular and crystal structure and spectroscopic and thermochemical properties of rifamycin OBacchi, Alessia; Pelizzi, Giancarlo; Nebuloni, Marino; Ferrari, PietroJournal of Medicinal Chemistry (1998), 41 (13), 2319-2332CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The mechanism of action of rifamycins against bacterial DNA-dependent RNA polymerase has been explained on the basis of the spatial arrangement of four oxygens which can form hydrogen bonds with the enzyme. Structural descriptors are derived from X-ray diffraction crystal structures of 25 active and nonactive rifamycins. Principal component anal. is used to find the combination of structural parameters which better discriminate between active and nonactive rifamycins. Two possible mechanisms of mol. rearrangement are described which can convert nonactive into active conformations. The energy involved for conformational rearrangements is studied by mol. modeling techniques. Me C34 is found to play a key role for detg. the geometry of the pharmacophore. Rifamycin O, reported to be active, is obtained by oxidn. of rifamycin B and is studied by X-ray single-crystal diffractometry, by soln. IR and NMR spectroscopy, and by thermal anal. Surprisingly the oxidn. process results are totally stereospecific, and an explanation is given based on soln. spectroscopic evidence. The conformation found in the solid state is typical of nonactive compds., and mol. mechanics calcns. show that a mol. rearrangement to the active conformation would require about 15 kcal/mol. Thermal anal. confirms that rifamycin O has a sterically constrained conformation. Therefore, it is likely that the antibiotic activity of rifamycin O is due either to chem. modification prior to reaching the enzyme or to conformational activation.
- 67Bergamini, N.; Fowst, G. Rifamycin SV. A review. Arzneim.-Forsch. 1965, 15 (Suppl), 951– 1002[CAS], Google Scholar67https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF2MXksl2rsb4%253D&md5=3d10d69f2e61468abed76d9383049f90Rifamycin SVBergamini, N.; Fowst, G.Arzneimittel-Forschung (1965), 15 (8a), 951-1002CODEN: ARZNAD; ISSN:0004-4172.400 refs.
- 68Rode, H. B.; Lade, D. M.; Grée, R.; Mainkar, P. S.; Chandrasekhar, S. Strategies towards the synthesis of anti-tuberculosis drugs. Org. Biomol. Chem. 2019, 17, 5428– 5459, DOI: 10.1039/C9OB00817A[Crossref], [PubMed], [CAS], Google Scholar68https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXoslKqs7s%253D&md5=8d8e84286dae61acd4adfe38142cf45fStrategies towards the synthesis of anti-tuberculosis drugsRode, Haridas B.; Lade, Dhanaji M.; Gree, Rene; Mainkar, Prathama S.; Chandrasekhar, SrivariOrganic & Biomolecular Chemistry (2019), 17 (22), 5428-5459CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)A review. Antituberculosis drugs have captured the attention of the scientific community due to the emergence of drug resistance. Hence, the development of new analogs and new drugs which can treat drug-resistant tuberculosis is required. In this report, we reviewed the strategies towards the synthesis of antituberculosis drugs. These strategies include semisynthetic approaches, resoln. based strategies, microbial transformations, solid phase synthesis, and asym. synthesis. As stereochem. is an important hallmark of many drugs, the strategies based on asym. synthesis are described in detail. The emphasis on semisynthetic approaches is given for aminoglycoside antibiotics.
- 69(a) Loos, U.; Musch, E.; Jensen, J. C.; Mikus, G.; Schwabe, H. K.; Eichelbaum, M. Pharmacokinetics of oral and intravenous rifampicin during chronic administration. Klin. Wochenschr. 1985, 63, 1205– 1211, DOI: 10.1007/BF01733779[Crossref], [PubMed], [CAS], Google Scholar.69ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL287hs1GltA%253D%253D&md5=0337fe0975b63bd2bd6ff69435d9e02ePharmacokinetics of oral and intravenous rifampicin during chronic administrationLoos U; Musch E; Jensen J C; Mikus G; Schwabe H K; Eichelbaum MKlinische Wochenschrift (1985), 63 (23), 1205-11 ISSN:0023-2173.We investigated the pharmacokinetics of rifampicin and its major metabolites, 25-desacetylrifampicin and 3-formylrifampicin, in two groups of six patients with active pulmonary tuberculosis, who received either multiple oral or intravenous rifampicin therapy in combination with intravenous isoniazid and ethambutol. Serum concentrations of rifampicin were each determined after a single oral and intravenous test dose of 600 mg rifampicin at the beginning and after 1 and 3 weeks of tuberculostatic treatment. Analysis of rifampicin and its metabolites was performed by high-pressure liquid chromatography. It was found that, due to autoinduction of its metabolizing hepatic enzymes, the systemic clearance of rifampicin increased from 5.69 to 9.03 l/h after 3 weeks of multiple dosing. The volume of distribution of the drug was constant over the period of this study. The bioavailability of the active, orally administered rifampicin decreased from 93% after the first single oral dose to 68% after 3 weeks of oral and intravenous rifampicin therapy. Relating to the increase in systemic (hepatic) clearance, a bioavailability no lower than 90% can be predicted. The reduction to 68% indicates that, in addition to an increase of hepatic metabolism, an induction of a prehepatic "first-pass" effect resulted from multiple rifampicin doses. Our study of rifampicin metabolites confirm that prehepatic metabolism was induced, since a higher metabolic ratio resulted after the oral doses than after the intravenous rifampicin test doses. A preabsorptive process can therefore be excluded as a cause of reduced bioavailability.(b) Acocella, G. Clinical pharmacokinetics of rifampicin. Clin. Pharmacokinet. 1978, 3, 108– 127, DOI: 10.2165/00003088-197803020-00002[Crossref], [PubMed], [CAS], Google Scholar69bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE1cXktFKms74%253D&md5=b7a697fe3dda6d470e0cb55306013207Clinical pharmacokinetics of rifampicinAcocella, G.Clinical Pharmacokinetics (1978), 3 (2), 108-27CODEN: CPKNDH; ISSN:0312-5963.A review with many refs. of rifampicin (I) [13292-46-1] clin. pharmacokinetics.
- 70Campbell, E. A.; Korzheva, N.; Mustaev, A.; Murakami, K.; Nair, S.; Goldfarb, A.; Darst, S. A. Structural mechanism for rifampicin inhibition of bacterial RNA polymerase. Cell 2001, 104, 901– 912, DOI: 10.1016/S0092-8674(01)00286-0[Crossref], [PubMed], [CAS], Google Scholar70https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXisVyis7s%253D&md5=e64b9de4f4f6f832d481608b1324b48fStructural mechanism for rifampicin inhibition of bacterial RNA polymeraseCampbell, Elizabeth A.; Korzheva, Nataliya; Mustaev, Arkady; Murakami, Katsuhiko; Nair, Satish; Goldfarb, Alex; Darst, Seth A.Cell (Cambridge, MA, United States) (2001), 104 (6), 901-912CODEN: CELLB5; ISSN:0092-8674. (Cell Press)Rifampicin (Rif) is one of the most potent and broad spectrum antibiotics against bacterial pathogens and is a key component of anti-tuberculosis therapy, stemming from its inhibition of the bacterial RNA polymerase (RNAP). We detd. the crystal structure of Thermus aquaticus core RNAP complexed with Rif. The inhibitor binds in a pocket of the RNAP β subunit deep within the DNA/RNA channel, but more than 12 Å away from the active site. The structure, combined with biochem. results, explains the effects of Rif on RNAP function and indicates that the inhibitor acts by directly blocking the path of the elongating RNA when the transcript becomes 2 to 3 nt in length.
- 71Brogden, R. N.; Fitton, A. Rifabutin. Drugs 1994, 47, 983– 1009, DOI: 10.2165/00003495-199447060-00008[Crossref], [PubMed], [CAS], Google Scholar71https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXls12ntbY%253D&md5=a8648ab5e2878b0ca2c47b13420d7725Rifabutin: a review of its antimicrobial activity, pharmacokinetic properties and therapeutic efficacyBrogden, Rex N.; Fitton, AndrewDrugs (1994), 47 (6), 983-1009CODEN: DRUGAY; ISSN:0012-6667.A review, with approx. 150 refs. Rifabutin is a deriv. of rifamycin S with activity against mycobacteria including atypical organisms such as Mycobacterium avium and M. intracellulare, also referred to as Mycobacterium avium-intracellulare complex (MAC). To date, rifabutin is the only drug to have been studied in large prospective placebo-controlled trials that has been shown to significantly reduce the incidence of disseminated MAC infection when administered prophylactically as a single agent to patients with acquired immune deficiency syndrome (AIDS). Initial studies also indicate that rifabutin may be a useful component of multiple drug regimens for the treatment of MAC infection, although further studies combining rifabutin with other recently available antimycobacterial drugs are required to det. the most effective regimens. When rifabutin is combined with at least two other antimycobacterial drugs, the combination appears to be of similar efficacy to rifampicin (rifampin)-contg. regimens in patients with newly diagnosed pulmonary tuberculosis. Since available therapy for MAC infection in patients with AIDS is still suboptimal, rifabutin, at present the only first-line agent for prophylaxis against disseminated MAC infection in patients with advanced human immunodeficiency virus (HIV) infection, has the potential to make a valuable contribution to the continuing attempts to preserve the quality of life of patients with AIDS.
- 72(a) Skinner, M. H.; Blaschke, T. F. Clinical pharmacokinetics of rifabutin. Clin. Pharmacokinet. 1995, 28, 115– 125, DOI: 10.2165/00003088-199528020-00003[Crossref], [PubMed], [CAS], Google Scholar.72ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2M3lsVOltQ%253D%253D&md5=f84f607d888d36c507d0983f02f88ce1Clinical pharmacokinetics of rifabutinSkinner M H; Blaschke T FClinical pharmacokinetics (1995), 28 (2), 115-25 ISSN:0312-5963.The clinical effectiveness of rifabutin for prophylaxis of disseminated Mycobacterium avium complex infection has recently been demonstrated in HIV-positive patients with low CD4 counts. Rifabutin is a newly marketed, semisynthetic antimycobacterial agent similar to rifampicin (rifampin) in structure and activity. However, rifabutin has important pharmacokinetic differences compared with rifampicin. Rifabutin has relatively low oral bioavailability; about 20% after single dose administration. With long term administration rifabutin induces its own metabolism and the metabolism of some other drugs. The elimination half-life of rifabutin is long (45 hours) but, as a result of a very large volume of distribution (> 9 L/kg), average plasma concentrations remain relatively low after repeated administration of standard doses. In vitro rifabutin is more active against M. avium-intracellulare complex and at least as active against M. tuberculosis as rifampicin. In vivo the advantage of rifabutin is less apparent due to its lower plasma concentrations at equivalent doses. Adverse effects are unusual at the recommended oral dosage of 300 mg/day, but become common as the total daily dose approaches 1 g. Dose-limiting toxicity consists of a polyarthralgia/arthritis syndrome, possibly complicated by uveitis. More clinical studies are needed to establish the role of rifabutin in combination therapy for M. avium-intracellulare complex and other mycobacterial infections.(b) Blaschke, T. F.; Skinner, M. H. The clinical pharmacokinetics of rifabutin. Clin. Infect. Dis. 1996, 22, S15– S22, DOI: 10.1093/clinids/22.Supplement_1.S15[Crossref], [PubMed], [CAS], Google Scholar72bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XisVGgur0%253D&md5=43441f1ef61aa1f820fe3b85022c8ef2The clinical pharmacokinetics of rifabutinBlaschke, Terrence F.; Skinner, Michael H.Clinical Infectious Diseases (1996), 22 (Suppl. 1), S15-S22CODEN: CIDIEL; ISSN:1058-4838. (University of Chicago Press)A review with 28 refs. Rifabutin is structurally similar to rifampin, but there are important pharmacokinetic differences between the 2 drugs. Rifabutin is more lipid sol. than is rifampin, resulting in more-extensive tissue uptake, a larger vol. of distribution, lower max. plasma concns., lower trough concns., a longer terminal half-life, and higher tissue-to-plasma drug concn. ratios. The oral bioavailability of rifabutin is low. Like rifampin, rifabutin induces its own metab. during multiple dosing. Rifabutin is extensively metabolized. The 2 major metabolites of rifabutin contribute to its antimicrobial activity.
- 73Stahelin, H. F.; von Wartburg, A. The chemical and biological route from podophyllotoxin glucoside to etoposide: ninth Cain Memorial Award Lecture. Cancer Res. 1991, 51, 5– 15[PubMed], [CAS], Google Scholar73https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK3M7gsFKktQ%253D%253D&md5=3a2d99d15f60c943d3c6cf31ec8f15e2The chemical and biological route from podophyllotoxin glucoside to etoposide: ninth Cain memorial Award lectureStahelin H F; von Wartburg ACancer research (1991), 51 (1), 5-15 ISSN:0008-5472.There is no expanded citation for this reference.
- 74(a) Joel, S. P.; Clark, P. I.; Heap, L.; Webster, L.; Robbins, S.; Craft, H.; Slevin, M. L. Pharmacological attempts to improve the bioavailability of oral etoposide. Cancer Chemother. Pharmacol. 1995, 37, 125– 133, DOI: 10.1007/BF00685639[Crossref], [PubMed], [CAS], Google Scholar.74ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XlvFyksQ%253D%253D&md5=d2bc8bca898d0a301999a8c1a234149ePharmacological attempts to improve the bioavailability of oral etoposideJoel, Simon P.; Clark, Peter I.; Heap, Laura; Webster, Lynn; Robbins, Sallie; Craft, Helen; Slevin, Maurice L.Cancer Chemotherapy and Pharmacology (1995), 37 (1/2), 125-33CODEN: CCPHDZ; ISSN:0344-5704. (Springer)Etoposide demonstrates incompletes and variable bioavailability after oral dosing, which may be due to its concn. and pH-dependent stability in artificial gastric and intestinal fluids. The use of agents that may influence etoposide stability and, thereby, bioavailability, was investigated in a no. of clin. studies. Drugs that influence the rate of gastric emptying, while modulating the time of drug absorption, did not significantly alter the etoposide area under the concn.-time curve (AUC) or bioavailability. Specifically, metoclopramide had little effect on the etoposide absorption profile and did not significantly alter the AUC (AUC with etoposide alone, 68.4 vs. 74.3 μg mL-1 h with metoclopramide), suggesting that in most patients the drug is already emptied rapidly from the stomach. In contrast, propantheline produced a dramatic effect on etoposide absorption, delaying the time of maximal concn. tmax from 1.1 to 3.5 h , but again without a significant improvement in drug AUC or bioavailability across the 24 h study period (AUC with etoposide alone 78.3, vs. 88.1 μg mL-1 h with propantheline). The effect of these drugs on the absorption of oral paracetamol, a drug included in the study as a marker of gastric emptying, was exactly the same as that found for etoposide, with no change in AUC being obsd. after metoclopramide or propantheline administration but a significant delay in tmax being seen on co-administration with etoposide and propantheline. The co-administration of ethanol or bile salts (agents that significantly improved the stability of etoposide in artificial intestinal fluid) with oral etoposide similarly had no effect on improving the etoposide AUC or reducing the variability in AUC, suggesting that drug stability in vivo was not affected by these agents. In the third study, the co-administration of cimetidine had no effect on the pharmacokinetics of oral or i.v. etoposide, despite the previous observation that the etoposide stability was markedly improved at pH 3-5 as compared with pH 1 in artificial gastric fluid. This series of studies, designed to investigate factors that improved etoposide stability in lab. studies, failed to demonstrate any potentially useful improvement in AUC or bioavailability in the clin. setting.(b) Shah, J. C.; Chen, J. R.; Chow, D. Preformulation study of etoposide: identification of physicochemical characteristics responsible for the low and erratic oral bioavailability of etoposide. Pharm. Res. 1989, 6, 408– 412, DOI: 10.1023/A:1015935532725[Crossref], [PubMed], [CAS], Google Scholar.74bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1MXkvVeqtL4%253D&md5=2b8afef71712ed9441c2ca02eec6c0baPreformulation study of etoposide: identification of physicochemical characteristics responsible for the low and erratic oral bioavailability of etoposideShah, Jaymin C.; Chen, Jivn R.; Chow, DianaPharmaceutical Research (1989), 6 (5), 408-12CODEN: PHREEB; ISSN:0724-8741.Preformulation studies of etoposide (I), including pH-soly. profile, partition coeff., pH-stability profile, and in vitro dissoln. kinetics, were conducted to identify the responsible factor(s) for the low and erratic oral bioavailability of I. A stability-indicating HPLC assay was used for drug monitoring. The equil. aq. soly. of I at 37° was low, 148.5-167.25 μg/mL, and did not vary over the pH range of 2 to 6. The pH-stability profile indicated rapid degrdn. of I at pH 1.3 and 10, with degrdn. half-lives of 2.88 and 3.83 h, resp., at 25°. The half-life at pH 7.30 was 27.72 days. Max. stability at 25° was reached at pH 5 to 6.15, with half-lives of 63 and 49.5 days, resp. The intrinsic dissoln. rate was slow, 0.0094 mg/min/cm2, while the I partition coeff. between n-octanol and water was 9.94. Therefore, I absorption appears to be dissoln. rate-limited rather than permeation rate-limited. The low equil. aq. soly., slow intrinsic dissoln. rate, and chem. instability at pH 1.3 could account for the low oral bioavailability.(c) Toffoli, G.; Corona, G.; Basso, B.; Boiocchi, M. Pharmacokinetic optimization of treatment with oral etoposide. Clin. Pharmacokinet. 2004, 43, 441– 466, DOI: 10.2165/00003088-200443070-00002[Crossref], [PubMed], [CAS], Google Scholar74chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXltlGjsLw%253D&md5=346f1cb2a0b8c46971b35793c3e16a86Pharmacokinetic optimisation of treatment with oral etoposideToffoli, Giuseppe; Corona, Giuseppe; Basso, Barbara; Boiocchi, MauroClinical Pharmacokinetics (2004), 43 (7), 441-466CODEN: CPKNDH; ISSN:0312-5963. (Adis International Ltd.)A review. Etoposide is a deriv. of podophyllotoxin widely used in the treatment of several neoplasms, including small cell lung cancer, germ cell tumors and non-Hodgkin's lymphomas. Prolonged administration of etoposide aims for continuous inhibition of topoisomerase II, the intracellular target of etoposide, thus preventing tumor cells from repairing DNA breaks. However, the clin. advantages of extended schedules as compared with conventional short-term infusions remain unclear. Oral administration of etoposide represents the most feasible and economic strategy to maintain effective concns. of drug for extended times. Nevertheless, the efficacy of oral etoposide therapy is contingent on circumventing pharmacokinetic limitations, mainly low and variable bioavailability. Inhibition of small bowel and hepatic metab. of etoposide with specific cytochrome P 450 inhibitors or inhibition of the intestinal P-glycoprotein efflux pump have been attempted to increase the bioavailability of oral etoposide, but the best results were obtained with daily oral administration of low etoposide doses (50-100 mg/day for 14-21 days). Saturable absorption of etoposide was reported for doses greater than 200 mg/day, whereas lower doses were assocd. with increased bioavailability, although they were characterized by high inter- and intrapatient variability. Pharmacokinetic parameters such as plasma trough concn. between two oral administrations (C24,trough), drug exposure time above a threshold value and area under the plasma concn.-time curve have been correlated with the pharmacodynamic effect of oral etoposide. Pharmacokinetic-pharmacodynamic relationships indicate that severe toxicity is avoided when peak plasma concns. do not exceed 3-5 mg/L and C24,trough is under the threshold limit of 0.3 mg/L. To maintain effective etoposide plasma concns. during prolonged oral administration, pharmacokinetic variability must be monitored in each patient, taking account of factors from many pharmacokinetic studies of etoposide, including absorption, distribution, protein binding, metab. and elimination. Dosage redn. is generally useful to avoid haematol. toxicity in patients with renal dysfunction (creatinine clearance <50 mL/min). The need for dosage adjustment based on liver function in patients with liver dysfunction is not completely defined, but generally is not indicated in patients with minor liver dysfunction. Adaptive dosage adjustment based on individual pharmacokinetic parameters, estd. using limited sampling strategies and population pharmacokinetic models, is more appropriate. This approach has been used with success in different clin. trials to increase the etoposide dosage, without significantly increasing toxicity. Various pharmacodynamic models have been proposed to guide etoposide oral dosage. However, they lack precision and accuracy and need to be refined by considering other predictor variables in order to extend their application in current clin. practice.
- 75(a) Saulnier, M. G.; Langley, D.; Kadow, J. F.; Senter, P. D.; Knipe, J.; Tun, M. M.; Vyas, D. M.; Doyle, T. W. Synthesis of etoposide phosphate, BMY-40481, a water-soluble clinically active prodrug of etoposide. Bioorg. Med. Chem. Lett. 1994, 4, 2567– 2572, DOI: 10.1016/S0960-894X(01)80285-7[Crossref], [CAS], Google Scholar.75ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXit1Orsrg%253D&md5=f7b1af24686a636b3d76115f14c224b9Synthesis of etoposide phosphate, BMY-40481: a water-soluble clinically active prodrug of etoposideSaulnier, Mark G.; Langley, David R.; Kadow, John F.; Senter, Peter D.; Knipe, Jay O.; Tun, Min Min; Vyas, Dolatrai M.; Doyle, Terrence W.Bioorganic & Medicinal Chemistry Letters (1994), 4 (21), 2567-72CODEN: BMCLE8; ISSN:0960-894X. (Elsevier)Etoposide phosphate (BMY-40481) I (R = PO3H2) is synthesized semi-synthetically from the clin. approved anticancer parent drug, etoposide (VP-16-213) I (R = H), and also from natural (-)-epipodophyllotoxin. Etoposide phosphate functions as a clin. active, water sol. prodrug of etoposide.(b) Chabot, G G; Armand, J P; Terret, C; de Forni, M; Abigerges, D; Winograd, B; Igwemezie, L; Schacter, L; Kaul, S; Ropers, J; Bonnay, M Etoposide bioavailability after oral administration of the prodrug etoposide phosphate in cancer patients during a phase I study. J. Clin. Oncol. 1996, 14, 2020– 2030, DOI: 10.1200/JCO.1996.14.7.2020[Crossref], [PubMed], [CAS], Google Scholar75bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XksFejt74%253D&md5=9c0d38ad2739bd812868ae1c99a82d01Etoposide bioavailability after oral administration of the prodrug etoposide phosphate in cancer patients during a phase I studyChabot, G. G.; Armand, J. -P.; Terref, C.; De Forni, M.; Abigerges, D.; Winograd, B.; Igwemezie, L.; Schacter, L.; Kaul, S.; et al.Journal of Clinical Oncology (1996), 14 (7), 2020-2030CODEN: JCONDN; ISSN:0732-183X. (Saunders)The purpose of this study was to det. the bioavailability (F) of etoposide (E; VP-16) after oral administration of the water-sol. prodrug etoposide phosphate (EP;BMY-40481) during a phase I trial in cancer patients. Patients and Methods: Twenty-nine patients received oral EP (capsules, 50 to 150 mg/M2/d of E equiv.) for 5 days in week 1 course (1), followed every 3 wk there-after by a daily i.v. (IV) infusion for 5 days of E (80 mg/M2, 1-h IV infusion; course (2)); in three patients, the IV E course was given before oral EP. Plasma and urine E pharmacokinetics (high-performance liq. chromatog. [HPLC]) were performed on the first day of oral EP administration and on the first day of IV E. Twenty-six of 29 patients completed two courses or more, whereas three patients received only one course due to toxicity. Myelosuppression was dose-dependent and dose-limiting, with grade 4 leukoneutropenia in four of 15 patients at 125 mg/M2 and in five of seven patients at 150 mg/M2. One patient died of meningeal hemorrhage related to grade 4 thrombocytopenia. Other toxicities were infrequent and/or manageable. No objective response was obsd. The max.-tolerated dose (MTD) is therefore 150 mg/M2, and the recommended oral dose of EP for phase II trials in this poor-risk patient population is 125 mg/M2. Twenty-six patients had pharmacokinetic data for both oral EP and IV E, whereas three had pharmacokinetic data on the IV E course only. After oral administration of EP, the pharmacokinetics of E were as follows: mean absorption rate const. (Ka), 1.7 h-1 (mean); lag time, 0.3 h; time of max. concn. (tmax), 1.6 h; and mean half-lives (t1/2), 1.6 (first) and 10.3 h (terminal); the increase in the area under the plasma concn.-vs.-time curve (AUC) of E was proportional to the EP dose. After the 1-h IV infusion of E, max. concn. (Cmax) was 15 μg/mL; mean AUC, 88.0 μg*h/mL; mean total-body clearance (CL), 0.97 L/h/M2 (16.2 mL/min/M2); and mean t1/2, 0.9 (first) and 8.1 h (terminal). The 24-h urinary excretion of E after IV E was significantly higher (33%) compared with that of oral EP (17%). Significant correlation was obsd. between the neutropenia at nadir and the AUC of E after oral EP administration (r =.58, sigmoid max. effect [Emax] model). The mean F of E after oral administration of EP in 26 patients was 68.0% (coeff. of variation [CV], 26.3%; F range, 35.5% to 111.8%). In this study, tumor type, as well as EP dose, did not significantly influence the F in E. There was no difference in F of E, whether oral EP was administered before or after IV E. Compared with literature data on oral E, the percent F in E after oral prodrug EP administration was 19% higher at either low (≤ 100 mg/M2) or high (> 100 mg/M2) doses. Similarly to E, the main toxicity of the prodrug EP is dose-dependent leukoneutropenia, which is dose-limiting at the oral MTD of 150 mg/M2/d for 5 days. The recommended oral dose of EP is 125 mg/M2/d for 5 days every 3 wk in poor-risk patients. Compared with literature data, oral EP has a 19% higher F value compared with oral E either at low or high doses. This higher F in E from oral prodrug EP appears to be a pharmacol. advantage that could be of potential pharmacodynamic importance for this drug.
- 76(a) Heimbach, T.; Oh, D.-M.; Li, L. Y; Rodrıguez-Hornedo, N.ır; Garcia, G.; Fleisher, D. Enzyme-mediated precipitation of parent drugs from their phosphate prodrugs. Int. J. Pharm. 2003, 261, 81– 92, DOI: 10.1016/S0378-5173(03)00287-4[Crossref], [PubMed], [CAS], Google Scholar.76ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXls1Sqs7o%253D&md5=48f6f7452f36afafa782eabb81936268Enzyme-mediated precipitation of parent drugs from their phosphate prodrugsHeimbach, Tycho; Oh, Doo-Man; Li, Lilian Y.; Rodriguez-Hornedo, Nair; Garcia, George; Fleisher, DavidInternational Journal of Pharmaceutics (2003), 261 (1-2), 81-92CODEN: IJPHDE; ISSN:0378-5173. (Elsevier Science B.V.)Many oral phosphate prodrugs have failed to improve the rate or extent of absorption compared to their insol. parent drugs. Rapid parent drug generation via intestinal alk. phosphatase can result in supersatd. solns., leading to parent drug pptn. The purpose was to (1) investigate whether parent drugs can ppt. from prodrug solns. in presence of alk. phosphatase; (2) det. whether induction times are influenced by (a) dephosphorylation rate, (b) parent drug supersatn. level, and (c) parent drug soly. Induction times were detd. from increases in optical densities after enzyme addn. to prodrug solns. of TAT-59, fosphenytoin and estramustine phosphate. Apparent supersatn. ratios (σ) were calcd. from parent drug soly. at intestinal pH. Pptn. could be generated for all three prodrugs. Induction times decreased with increased enzyme activity and supersatn. level and were within gastrointestinal (GI) residence times for TAT-59 concn.≥21 μM (σ≥210). Induction times for fosphenytoin were less than the GI residence time (199 min) for concns. of approx. 352 μM (σ=4.0). At approx. 475 μM (σ=5.3) the induction times were less than 90 min. For estramustine-phosphate, no pptn. was obsd. within GI residence times. Enzyme-mediated pptn. will depend on apparent supersatn. ratios, parent drug dose, soly. and solubilization by the prodrug.(b) Heimbach, T.; Oh, D. M.; Li, L. Y.; Forsberg, M.; Savolainen, J.; Leppänen, J.; Matsunaga, Y.; Flynn, G.; Fleisher, D. Absorption rate limit considerations for oral phosphate prodrugs. Pharm. Res. 2003, 20, 848– 856, DOI: 10.1023/A:1023827017224[Crossref], [PubMed], [CAS], Google Scholar76bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXjvFyisrg%253D&md5=954bff3aa76b382614901161042f5cd9Absorption Rate Limit Considerations for Oral Phosphate ProdrugsHeimbach, Tycho; Oh, Doo-Man; Li, Lilian Y.; Forsberg, Markus; Savolainen, Jouko; Leppaenen, Jukka; Matsunaga, Yasushi; Flynn, Gordon; Fleisher, DavidPharmaceutical Research (2003), 20 (6), 848-856CODEN: PHREEB; ISSN:0724-8741. (Kluwer Academic/Plenum Publishers)The potential of phosphate ester prodrugs to significantly improve the absorptive flux of poorly sol. parent drugs was evaluated. Absorptive transport studies of parent drugs and their prodrugs were carried out in Caco-2 cells. Prodrugs of parent drugs with variable aq. solubilities were tested: Hydrocortisone-phosphate/Hydrocortisone, Fosphenytoin/phenytoin, TAT-59/DP-TAT-59, and Entacapone phosphate/Entacapone. Addnl. absorption studies were carried out in rats. Absorptive fluxes of DP-TAT-59 and phenytoin increased 9.8 or 3.3-fold after dosing TAT-59 and 500 μM fosphenytoin, resp. Hydrocortisone's flux did not increase with hydrocortisone-phosphate at 100 μM. Permeability of the highly lipophilic and protein bound compd., DP-TAT-59, was significantly increased with serosal albumin. No permeability increase was obsd. for the other drugs with albumin. Entacapone phosphate failed to improve the flux of entacapone compared to an entacapone soln., but the prodrug soln. did yield higher entacapone plasma levels in rats when compared with an entacapone suspension. Ideal phosphate prodrug candidates are characterized by high permeability and low soly. (BCS Class II drugs). For low dose BCS Class II drug candidates, however, no biopharmaceutical advantage may be gained. Phosphate prodrugs of parent drugs with limited permeability may fail. When screening highly lipophilic parent drugs transport studies should be done with albumin.
- 77Long, B. H. Mechanisms of action of teniposide (VM-26) and comparison with etoposide (VP-16). Semin. Oncol. 1992, 19 (Suppl. 6), 3– 19[PubMed], [CAS], Google Scholar77https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK3s%252FjtVyqtw%253D%253D&md5=1d2ac6451a47f7ce371cb2ed7bfa36a2Mechanisms of action of teniposide (VM-26) and comparison with etoposide (VP-16)Long B HSeminars in oncology (1992), 19 (2 Suppl 6), 3-19 ISSN:0093-7754.Teniposide is the result of extensive, long-term efforts to refine and improve on the cytotoxic activity of naturally occurring compounds extracted from podophyllin resins and purified. Isolation of an extremely potent though minor component of one of the early podophyllin derivatives led in turn to the synthesis and evaluation of several aldehyde condensation products. Two of these, teniposide and etoposide, were further investigated when their considerable antitumor activity in animals became apparent. Recognition of transient DNA breaks induced by teniposide, etoposide, and other podophyllotoxin analogues established not only that their site of activity was DNA but also that their cytotoxic effect was dose-dependent. Extensive investigation has further indicated that a primary mechanism of action of these agents involves inhibition of the catalytic activity of eukaryote topoisomerase II and, more important, the consequent stabilization of the normally transient covalent intermediate formed between the DNA substrate and the enzyme. As a result of elevated enzyme levels or enzyme activity, or both, in transformed cells, topoisomerase II inhibitors are highly selective for cancer cells versus normal cells. Although teniposide is not substantially more potent than etoposide in terms of catalytic inhibition or stabilization of the DNA-enzyme intermediate, it is more readily taken up by cells, which results in greater teniposide accumulation within the cells and, thus, a greater capacity for cytotoxicity.
- 78(a) Splinter, T. A.; Holthuis, J. J.; Kok, T. C.; Post, M. H. Absolute bioavailability and pharmacokinetics of oral teniposide. Semin. Oncol. 1992, 19 (Suppl. 6), 28– 34[PubMed], [CAS], Google Scholar.78ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK3s%252FjtVyqtg%253D%253D&md5=764b15a70053192998cb6decc15365a8Absolute bioavailability and pharmacokinetics of oral teniposideSplinter T A; Holthuis J J; Kok T C; Post M HSeminars in oncology (1992), 19 (2 Suppl 6), 28-34 ISSN:0093-7754.The absolute bioavailability and pharmacokinetics of orally administered teniposide were investigated in 25 patients. All patients received 50 to 60 mg/m2 teniposide intravenously on day 1, before oral administration. Six patients received 60 mg/m2 as a single oral dose on day 8; 5 patients received 60 mg/m2 and 120 mg/m2 as a single oral dose on days 8 and 15, respectively; 5 patients received 120 mg/m2 and 240 mg/m2 as a single oral dose on days 8 and 15, respectively; 6 patients received 60 mg/m2 as a single oral dose on 5 consecutive days from days 8 to 12; and 3 patients received 50 mg/m2 three times a day at 6-hour intervals on day 8. The mean absolute bioavailability was 41.6% +/- 14.2% with a large interindividual variability (range, 19.7% to 71.4%) and a low intraindividual variability (range, 2.8% to 13.9%). At a dose of 240 mg/m2, the bioavailability was decreased, whereas administration of multiple doses on 1 day or 5 consecutive days increased the overall bioavailability. In conclusion, teniposide can be administered orally with a bioavailability comparable with that of etoposide. The schedule dependency of both drugs warrants investigations of oral administration for 21 or more days. A formulation of teniposide capsules of 50 mg or less would be most helpful to facilitate oral administration.(b) Relling, M. V.; Evans, R.; Dass, C.; Desiderio, D. M.; Nemec, J. Human cytochrome P450 metabolism of teniposide and etoposide. J. Pharmacol. Exp. Ther. 1992, 261, 491– 496[PubMed], [CAS], Google Scholar78bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK38XktF2rsb8%253D&md5=21596e6fc82edd14fed6c600d15cfe8fHuman cytochrome P450 metabolism of teniposide and etoposideRelling, Mary V.; Evans, Robert; Dass, Chhabil; Desiderio, Dominic M.; Nemec, JosefJournal of Pharmacology and Experimental Therapeutics (1992), 261 (2), 491-6CODEN: JPETAB; ISSN:0022-3565.Although teniposide (VM26) and etoposide (VP16) are eliminated mostly by nonrenal mechanisms, their cytochrome P 450 metab. in humans has not been reported. The objective of this study was to det. the affinity and capacity of P 450 O-demethylation of VM26 and VP16 in a variety of human livers. Formation of catechols of VM26 and VP16 was detected in 24 and 26 of 26 liver microsomal prepns., resp., with wide variability in max. catechol formation rates from VM26 (41-fold) and VP16 (30-fold range), even among normal livers. Maximal activity measurements at 500 μM substrate were lower for VM26 catechol formation (mean = 1.5 nmol/mg/h) than for VP16 catechol (mean = 3.2 nmol/mg/h) in 26 livers. Maximal activities for VP16 and VM26 O-demethylation, and ethoxycoumarin O-deethylation were significantly higher in normal than in diseased livers. No differences were found in activities related to age, sex or race of the liver donor. In all five livers tested over a range of substrate concns., Km (19.7, 23.2, 43.5, 30.1 and 22.0 μM) and Vmax values (1.0, 1.2, 4.4, 8.2 and 4.0 nmol/mg/h) for VM26 were lower compared to values for VP16 (Km - 60.2, 115.1, 87.3, 42.1 and 81.9 μM; Vmax = 1.4, 3.3, 10.3, 27.5 and 10.1 nmol/mg/h). Despite higher VP16 catechol formation, VM26 underwent greater overall reduced NADP-dependent metab. than VP16, consistent with greater nonrenal clearance of VM26 in vivo. In addn. to the role of O-demethylation as a route of catabolism for VM26 and VP16 in humans, the significant variability in formation of the reactive catechol metabolites may play a role in their clin. efficacy and toxicity.
- 79Jacob, D. A.; Mercer, S. L.; Osheroff, N.; Deweese, J. E. Etoposide quinone is a redox-dependent topoisomerase II poison. Biochemistry 2011, 50, 5660– 5667, DOI: 10.1021/bi200438m[ACS Full Text], [CAS], Google Scholar79https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXmvFSlt70%253D&md5=f2314e9bb986d49398b568690295ea6eEtoposide Quinone Is a Redox-Dependent Topoisomerase II PoisonJacob, David A.; Mercer, Susan L.; Osheroff, Neil; Deweese, Joseph E.Biochemistry (2011), 50 (25), 5660-5667CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)Etoposide is a topoisomerase II poison that is used to treat a variety of human cancers. Unfortunately, 2-3% of patients treated with etoposide develop treatment-related leukemias characterized by 11q23 chromosomal rearrangements. The mol. basis for etoposide-induced leukemogenesis is not understood but is assocd. with enzyme-mediated DNA cleavage. Etoposide is metabolized by CYP3A4 to etoposide catechol, which can be further oxidized to etoposide quinone. A CYP3A4 variant is assocd. with a lower risk of etoposide-related leukemias, suggesting that etoposide metabolites may be involved in leukemogenesis. Although etoposide acts at the enzyme-DNA interface, several quinones poison topoisomerase II via redox-dependent protein adduction. The effects of etoposide quinone on topoisomerase IIα-mediated DNA cleavage have been examd. previously. Although findings suggest that the activity of the quinone is slightly greater than that of etoposide, these studies were carried out in the presence of significant levels of reducing agents (which should reduce etoposide quinone to the catechol). Therefore, the authors examd. the ability of etoposide quinone to poison human topoisomerase IIα in the absence of reducing agents. Under these conditions, etoposide quinone was ∼5-fold more active than etoposide at inducing enzyme-mediated DNA cleavage. Consistent with other redox-dependent poisons, etoposide quinone inactivated topoisomerase IIα when incubated with the protein prior to DNA and lost activity in the presence of dithiothreitol. Unlike etoposide, the quinone metabolite did not require ATP for maximal activity and induced a high ratio of double-stranded DNA breaks. The authors' results support the hypothesis that etoposide quinone contributes to etoposide-related leukemogenesis.
- 80Yang, J.; Bogni, A.; Schuetz, E. G.; Ratain, M.; Dolan, M. E.; McLeod, H.; Gong, L.; Thorn, C.; Relling, M. V.; Klein, T. E.; Altman, R. B. Etoposide pathway. Pharmacogenet. Genomics 2009, 19, 552– 553, DOI: 10.1097/FPC.0b013e32832e0e7f[Crossref], [PubMed], [CAS], Google Scholar80https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXntlOhtrs%253D&md5=f7837171ab20246dfa0b962787ade0edEtoposide pathwayYang, Jun; Bogni, Alessia; Schuetz, Erin G.; Ratain, Mark; Eileen Dolan, M.; McLeod, Howard; Gong, Li; Thorn, Caroline; Relling, Mary V.; Klein, Teri E.; Altman, Russ B.Pharmacogenetics and Genomics (2009), 19 (7), 552-553CODEN: PGHEAI; ISSN:1744-6872. (Lippincott Williams & Wilkins)A review. Antitumor etoposide effects and disposition are summarized.
- 81Pui, C. H.; Ribeiro, R. C.; Hancock, M. L.; Rivera, G. K.; Evans, W.; Raimondi, S. C.; Head, D. R.; Behm, F. G.; Mahmoud, M. H.; Sandlund, J. T.; Crist, W. M. Acute myeloid leukemia in children treated with epipodophyllotoxins for acute lymphoblastic leukemia. N. Engl. J. Med. 1991, 325, 1682– 1687, DOI: 10.1056/NEJM199112123252402[Crossref], [PubMed], [CAS], Google Scholar81https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK38%252FkvFKiuw%253D%253D&md5=9610ef0c41b7933f571f40bc0aedf074Acute myeloid leukemia in children treated with epipodophyllotoxins for acute lymphoblastic leukemiaPui C H; Ribeiro R C; Hancock M L; Rivera G K; Evans W E; Raimondi S C; Head D R; Behm F G; Mahmoud M H; Sandlund J TThe New England journal of medicine (1991), 325 (24), 1682-7 ISSN:0028-4793.BACKGROUND AND METHODS: Treatment of cancer with the epipodophyllotoxins (etoposide and teniposide) has been linked to the development of acute myeloid leukemia (AML) in children and adults, but the factors that might influence the risk of this complication of therapy are poorly defined. We therefore assessed the importance of potential risk factors for secondary AML in 734 consecutive children with acute lymphoblastic leukemia who attained complete remission and received continuation (maintenance) treatment according to different schedules of epipodophyllotoxin administration. RESULTS: Secondary AML was diagnosed in 21 of the 734 patients, in 17 of whom this complication was the initial adverse event. Prolonged administration of epipodophyllotoxin (teniposide with or without etoposide) twice weekly or weekly was independently associated with the development of secondary AML (P less than 0.01 by Cox regression analysis). The overall cumulative risk of AML at six years was 3.8 percent (95 percent confidence interval, 2.3 percent to 6.1 percent); but within the subgroups treated twice weekly or weekly, the risks were 12.3 percent (95 percent confidence interval, 5.7 percent to 25.4 percent) and 12.4 percent (95 percent confidence interval, 6.1 percent to 24.4 percent), respectively. In the subgroups not treated with epipodophyllotoxins or treated with them only during remission induction or every two weeks during continuation treatment, the highest cumulative risk was 1.6 percent (95 percent confidence interval, 0.4 percent to 6.1 percent). After adjustment for treatment frequency, there was no apparent relation between the total dose of epipodophyllotoxins and the development of secondary AML. The relative hazard of etoposide as compared with teniposide could not be determined. CONCLUSIONS: The risk of epipodophyllotoxin-related AML depends largely on the schedule of drug administration. Other factors, including the cumulative dose of epipodophyllotoxin, radiotherapy, and the initial biologic features of the leukemic blast cells, do not appear to have critical roles.
- 82Ashton, M. J.; Lawrence, C.; Karlsson, J.; Stuttle, K. A.; Newton, C. G.; Vacher, B. Y.; Webber, S.; Withnall, M. J. Anti-inflammatory 17β-thioalkyl-16α,17α-ketal and -acetal androstanes: a new class of airway selective steroids for the treatment of asthma. J. Med. Chem. 1996, 39, 4888– 4896, DOI: 10.1021/jm9604639[ACS Full Text], [CAS], Google Scholar82https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XmvVWnsbw%253D&md5=bbf0a7782e09994e5a55b4cba011520cAnti-inflammatory 17β-Thioalkyl-16α,17α-ketal and -acetal Androstanes: A New Class of Airway Selective Steroids for the Treatment of AsthmaAshton, Michael J.; Lawrence, Christopher; Karlsson, Jan-Anders; Stuttle, Keith A. J.; Newton, Christopher G.; Vacher, Bernard Y. J.; Webber, Stephen; Withnall, Michael J.Journal of Medicinal Chemistry (1996), 39 (25), 4888-4896CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The synthesis and anti-inflammatory potencies of a new class of 17β-thioalkyl-16α,17α-ketal and -acetal androstanes, e.g. I [R1 - R3 = Me, X = H, F; R1 = H, R2 = Pr, R3 = Me, X = H, F; R1 = X = H, R2 = Pr, R3 = Et, CHMe2; R1 = X = H, R2 = (E)-CH:CHMe, R3 = Me], are described. This new class of steroids was made by fragmentation of 2-thioxo-1,2-dihydropyrid-1-yl esters of the corresponding 17-acids to the 17-radical. The radical generated was trapped using a variety of radicophilic disulfides, giving a steroidal D-ring having acetal or ketal functionality at C-16 and C-17, together with a sulfide link at C-17. Compds. from this series bind to the glucocorticoid receptor with high potency and are functional agonists as measured by their ability to induce tyrosine aminotransferase activity in a rat hepatic cell line in vitro. These 17β-thioalkyl androstanes potently inhibit Sephadex-induced rat lung inflammation when administered directly into the airways. The high topical potency, together with a low propensity to induce systemic glucocorticoid-like side effects (rat thymus involution), provides the present compds. with a high degree of airway selectivity compared with currently available inhaled glucocorticoids. The presently described 17β-thioalkyl-16α,17α-ketal androstanes may be useful for therapies for inflammatory diseases such as asthma.
- 83(a) Gupta, R.; Jindal, D. P.; Kumar, G. Corticosteroids: the mainstay in asthma therapy. Bioorg. Med. Chem. 2004, 12, 6331– 6342, DOI: 10.1016/j.bmc.2004.05.045[Crossref], [PubMed], [CAS], Google Scholar.83ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhtVSnsr3M&md5=6c47f83d5ce6a033a15ba096ef336ba5Corticosteroids: the mainstay in asthma therapyGupta, Ranju; Jindal, Dharam Paul; Kumar, GulshanBioorganic & Medicinal Chemistry (2004), 12 (24), 6331-6342CODEN: BMECEP; ISSN:0968-0896. (Elsevier Ltd.)A review. Inflammation is now marked as a central feature of asthma pathophysiol. and aims of current asthma management are not only to treat acute symptoms of wheezing, breathlessness, chest tightness, cough but also to suppress the underlying inflammatory component. Despite the availability of a no. of drugs, corticosteroids remain the mainstay in the management of all types of asthma as these are the most potent and effective antiinflammatory agents available so far. Corticosteroids suppress virtually every step in inflammation. However therapeutic doses of oral glucocorticoids are assocd. with a range of adverse reactions. To overcome these side effects, inhalations have been developed to deliver glucocorticoids directly to the lungs and in the process a no. of aerosol prepns. have become available, which have advantage of significantly lower toxicity due to low systemic absorption from the respiratory tract and rapid inactivation. Despite considerable efforts by pharmaceutical industry, it has been difficult to develop novel therapeutic agents for asthma management, which could surpass inhaled corticosteroids. Currently the data favors using inhaled corticosteroids as monotherapy in the majority of patients in all kinds of asthma. If combination therapy is recommended to achieve addnl. control in severe asthma cases, other drugs such as β-agonists, antileukotrienes, theophylline, etc. are considered as adjunct therapies to corticosteroids. This review discusses the importance of corticosteroids as first line therapy for asthma treatment with the availability of inhaled corticosteroids for chronic treatment and oral formulations for treating acute exacerbations of moderate to severe asthma.(b) Ye, Q.; He, X.; D’Urzo, A. A review on the safety and efficacy of inhaled corticosteroids in the management of asthma. Pulmon. Ther. 2017, 3, 1– 18, DOI: 10.1007/s41030-017-0043-5
- 84Edsbäcker, S.; Andersson, P.; Lindberg, C.; Ryrfeldt, A.; Thalén, A. Metabolic acetal splitting of budesonide. A novel inactivation pathway for topical glucocorticoids. Drug Metab. Dispos. 1987, 15, 412– 417[PubMed], [CAS], Google Scholar84https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL2s3nsFCitg%253D%253D&md5=fa1c2afa97713d477501709b6fef4ecaMetabolic acetal splitting of budesonide. A novel inactivation pathway for topical glucocorticoidsEdsbacker S; Andersson P; Lindberg C; Ryrfeldt A; Thalen ADrug metabolism and disposition: the biological fate of chemicals (1987), 15 (3), 412-7 ISSN:0090-9556.Topical glucocorticoids usually have a high intrinsic glucocorticoid potency and may, after systemic uptake, induce side effects. The systemic inactivation of budesonide is rapid due to extensive liver biotransformation. The major metabolic pathway, 16 alpha, 17 alpha-acetal splitting, is unique for budesonide within this group of compounds. This biotransformation is catalyzed by microsomal monooxygenases and proceeds via hydroxylation and subsequent rearrangement to an intermediary ester. The ester is cleaved by hydrolysis to 16 alpha-hydroxyprednisolone and butyric acid. The hydrolysis product 16 alpha-hydroxyprednisolone has strongly reduced glucocorticoid activity.
- 85Spencer, C. M.; McTavish, D. A review of its pharmacological properties and therapeutic efficacy in inflammatory bowel disease. Drugs 1995, 50, 854– 872, DOI: 10.2165/00003495-199550050-00006[Crossref], [PubMed], [CAS], Google Scholar85https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28Xit12ntA%253D%253D&md5=ad52e162d2c723429dad116abcb9f233Budesonide: A review of its pharmacological properties and therapeutic efficacy in inflammatory bowel diseaseSpencer, Caroline M.; McTavish, DonnaDrugs (1995), 50 (5), 854-72CODEN: DRUGAY; ISSN:0012-6667. (Adis)A review with 51 refs. Budesonide is a glucocorticoid with high topical activity, but low systemic bioavailability which results in reduced systemic effects in comparison with other glucocorticoids. To date, it has been evaluated for use in patients with inflammatory bowel disease when administered either orally as a controlled ileal release formulation or rectally as an enema. In comparative trials, daily treatment with budesonide enema 2 mg/100mL for 4 wk produced endoscopic remission or improvement in 46 to 84% of patients with active distal ulcerative colitis and/or proctitis and histol. remission or improvement in 45 to 68%. In general, this regimen was a effective as regimens of hydrocortisone, methylprednisolone, prednisolone or mesalazine (5-amino-salicylic acid, mesalamine) enemas, but caused less suppression of plasma cortisol levels than the other glucocorticoids. Oral treatment with controlled release budesonide 9 mg/day for 8 wk produces clin. remission in 42 to 67% of patients with active Crohn's disease of the ileum, ileocecal region and/or ascending colon and significantly reduces Crohn's disease activity index scores compared with baseline and placebo. Results of a quality-of-life questionnaire reflected these clin. improvements. Budesonide has similar efficacy to prednisolone. Response to budesonide is maintained after dosage tapering at 8 wk. Compared with placebo, maintenance treatment with oral budesonide 3 or 6 mg/day increases the duration of remission in patients with Crohn's disease, but does not appear to affect the 1-yr relapse rate. Thus, budesonide, administered rectally to patients with distal ulcerative colitis or proctitis or orally to patients with Crohn's disease of the ileum, ileocecal region and/or ascending colon, is a favorable option for the treatment of acute exacerbations of inflammatory bowel disease. Because of the low incidence of adverse glucocorticoid-related effects assocd. with oral budesonide, it may also be a useful agent for longer term maintenance therapy if further clin. trials confirm its efficacy in this indication.
- 86de Weger, V. A.; Beijnen, J. H.; Schellens, J. H. M. Cellular and clinical pharmacology of the taxanes docetaxel and paclitaxel - a review. Anti-Cancer Drugs 2014, 25, 488– 494, DOI: 10.1097/CAD.0000000000000093[Crossref], [PubMed], [CAS], Google Scholar86https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXls1Glt7c%253D&md5=0e4cf76a8c1762913aeec74c616d6870Cellular and clinical pharmacology of the taxanes docetaxel and paclitaxel - a reviewde Weger, Vincent A.; Beijnen, Jos H.; Schellens, Jan H. M.Anti-Cancer Drugs (2014), 25 (5), 488-494CODEN: ANTDEV; ISSN:0959-4973. (Lippincott Williams & Wilkins)A review. Paclitaxel and docetaxel are active against a range of human cancers. Their antitumor activity is based on stabilization of the microtubule dynamics and thereby disruption of the cell cycle. The taxanes are administered as i.v. solns. in a short administration schedule. Distribution of both taxanes is rapid, with large vols. of distribution and significant binding to plasma proteins. The metab. of paclitaxel is mediated primarily by the P 450 cytochrome enzymes CYP2C8 and CYP3A, whereas docetaxel is only metabolized by CYP3A4. The most common toxicities after i.v. administration are neutropenia, hypersensitivity reactions, neurotoxicity, and alopecia. Several new administration forms are in development; albumin-bound paclitaxel (Abraxane) has recently been registered. Oral formulations of taxanes have been developed, and several are now undergoing phase I trials. New formulations might improve efficacy and safety and could be easier to use.
- 87(a) Yassine, F.; Salibi, E.; Gali-Muhtasib, H. Overview of the formulations and analogues in the taxanes&. story. Curr. Med. Chem. 2016, 23, 4540– 4558, DOI: 10.2174/0929867323666160907124013[Crossref], [PubMed], [CAS], Google Scholar.87ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXjs1eluw%253D%253D&md5=7028bbbdcb2e83c90b0ccf822922687cOverview of the Formulations and Analogs in the Taxanes'; StoryYassine, Farah; Salibi, Elia; Gali-Muhtasib, HalaCurrent Medicinal Chemistry (2016), 23 (40), 4540-4558CODEN: CMCHE7; ISSN:0929-8673. (Bentham Science Publishers Ltd.)Taxanes are a family of diterpenes produced by the yews (Taxus genus) that are extensively used in chemotherapy. The family encompasses paclitaxel, docetaxel and the recently added cabazitaxel, all of which were proven to be promising anti-cancer drugs. Due to the over harvesting danger threatening the yew trees as well as the many challenges faced by taxane-based chemotherapy, new formulations, analogs and delivery systems are required. Here, we undertook a structured search of the bibliog. database PubMed for peer reviewed research papers relying on key words and date of publication and organized the information based on the method of taxane drug delivery. Papers retrieved were from journals with significant impact and comparable scope. A total of 126 papers were reviewed, 81 of which published work related to the taxane formulations and nanoparticles, and 22 focused on the analogs derived from the three taxanes. Although recent articles investigate the effectiveness of taxane formulations, most of these formulations are still at the pre-clin. level. However, many of the taxane analogs are currently in clin. trials as second line treatment of aggressive cancers or are used in combination with other chemotherapeutic drugs. The findings corroborate the importance of developing new drug delivery strategies and taxane analogs to improve the efficacy of currently used chemotherapeutic drugs. This finding is further supported by the FDA-approved formulation of paclitaxel that eliminates the need for toxic solvents for drug administration, and the docetaxel analog cabazitaxel which has decreased affinity for efflux pumps.(b) Yared, J. A.; Tkaczuk, K. H. R. Update on taxane development: new analogues and new formulations. Drug Des., Dev. Ther. 2012, 6, 371– 384, DOI: 10.2147/DDDT.S28997[Crossref], [PubMed], [CAS], Google Scholar.87bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvFSlu7vI&md5=e43b35c36438e05fe2763bd3e2162a24Update on taxane development: new analogs and new formulationsYared, Jean A.; Tkaczuk, Katherine H. R.Drug Design, Development and Therapy (2012), 6 (), 371-384CODEN: DDDTAQ; ISSN:1177-8881. (Dove Medical Press Ltd.)A review. The taxanes (paclitaxel and docetaxel) represent an important class of antineoplastic agents that interfere with microtubule function leading to altered mitosis and cellular death. Paclitaxel (Taxol) was originally extd. from a yew tree (Taxus spp., Taxaceae) a small slow-growing evergreen, coniferous tree. Due to the initial scarcity of paclitaxel, docetaxel (Taxotere) a semisynthetic analog of paclitaxel produced from the needles of European yew tree, Taxus baccata was developed. Docetaxel differs from paclitaxel in two positions in its chem. structure and this small alteration makes it more water sol. Today, paclitaxel and docetaxel are widely prescribed antineoplastic agents for a broad range of malignancies including lung cancer, breast cancer, prostate cancer, Kaposi's sarcoma, squamous cell carcinoma of the head and neck, gastric cancer, esophageal cancer, bladder cancer, and other carcinomas. Although very active clin., paclitaxel and docetaxel have several clin. problems including poor drug soly., serious dose-limiting toxicities such as myelosuppression, peripheral sensory neuropathy, allergic reactions, and eventual development of drug resistance. A no. of these side effects have been assocd. with the solvents used for diln. of these antineoplastic agents: Cremophor EL for paclitaxel and polysorbate 80 for docetaxel. In addn., reports have linked these solvents to the alterations in paclitaxel and docetaxel pharmacokinetic profiles. In this review, we provide preclin. and clin. data on several novel taxanes formulations and analogs which are currently US Food and Drug Administration (FDA)-approved or in clin. development in various solid tumor malignancies. Of the new taxanes nab-paclitaxel and cabazitaxel have enjoyed clin. success and are FDA-approved; while many of the other compds. described in this review are unlikely to be further developed for clin. use in daily practice. Furthermore, the successful clin. emergence of novel nontaxane microtubule-targeting chemotherapy agents such as epothilones and eribulin is liable to further restrict the development of novel taxanes.(c) Baker, A. F.; Dorr, R. T. Drug interactions with the taxanes: clinical implications. Cancer Treat. Rev. 2001, 27, 221– 233, DOI: 10.1053/ctrv.2001.0228[Crossref], [PubMed], [CAS], Google Scholar87chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXnt1SktLo%253D&md5=b374723b96807c5c10862a7a20cb0eb7Drug interactions with the taxanes: Clinical implicationsBaker, A. F.; Dorr, R. T.Cancer Treatment Reviews (2001), 27 (4), 221-233CODEN: CTREDJ; ISSN:0305-7372. (W. B. Saunders)A review. The taxanes paclitaxel and docetaxel are among the most active antitumor agents. Clin. important pharmacodynamic interactions have been reported to occur with these agents that are sequence or schedule dependent. Because the taxanes undergo hepatic oxidn. via the cytochrome P 450 system, pharmacokinetic interactions due to enzyme induction or inhibition can also occur. A comprehensive literature search was conducted using Medline to identify clin. important drug-interactions with the taxanes. Clin. significant taxane interactions were identified for carboplatin, cisplatin, doxorubicin, docetaxel, epirubicin and anticonvulsants. Doxorubicin and epirubicin should be administered 24h before paclitaxel, and the cumulative anthracycline dose limited to 360 mg/m2. This will prevent the enhanced toxicities due to sequence and schedule dependent interactions between anthracyclines and paclitaxel. Conversely, paclitaxel should be administered at least 24h before cisplatin to avoid a decrease in clearance and increase in myelosuppression. With concurrent anticonvulsant therapy, cytochrome P 450 enzyme induction results in decreased paclitaxel plasma steady state concns., possibly requiring an increased dose of paclitaxel. A no. of other drug interactions have been reported in preliminary studies for which clin. significance has yet to be established. Clin. significant drug interactions have been reported to occur when paclitaxel is administered with doxorubicin, cisplatin, or anticonvulsants (phenytoin, carbamazepine, and phenobarbital).
- 88(a) Ishiyama, T.; Iimura, S.; Ohsuki, S.; Uoto, K.; Terasawa, H.; Soga, T. New highly active taxoids from 9β-dihydrobaccatin-9,10-acetals. Bioorg. Med. Chem. Lett. 2002, 12, 1083– 1086, DOI: 10.1016/S0960-894X(02)00069-0[Crossref], [PubMed], [CAS], Google Scholar.88ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XitFWhsbk%253D&md5=7c8653a32138e78497e0ef269fec81d6New highly active taxoids from 9β-Dihydrobaccatin-9,10-acetalsIshiyama, Takashi; Iimura, Shin; Ohsuki, Satoru; Uoto, Kouichi; Terasawa, Hirofumi; Soga, TsunehikoBioorganic & Medicinal Chemistry Letters (2002), 12 (7), 1083-1086CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)To synthesize new highly active taxoids, we designed and synthesized 9β-dihydro-9,10-acetal taxoids. In vitro study of these analogs, e.g. (I), clearly showed them to be more potent than docetaxel.(b) Ishiyama, T.; Iimura, S.; Yoshino, T.; Chiba, J.; Uoto, K.; Terasawa, H.; Soga, T. New highly active taxoids from 9β-dihydrobaccatin-9,10-acetals. Part 2. Bioorg. Med. Chem. Lett. 2002, 12, 2815– 2819, DOI: 10.1016/S0960-894X(02)00628-5[Crossref], [PubMed], [CAS], Google Scholar.88bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38Xntlansrc%253D&md5=1988e89f47dc19cb3ba4bcd3deb6897aNew highly active taxoids from 9β-dihydrobaccatin-9,10-acetals. Part 2Ishiyama, Takashi; Iimura, Shin; Yoshino, Toshiharu; Chiba, Jun; Uoto, Kouichi; Terasawa, Hirofumi; Soga, TsunehikoBioorganic & Medicinal Chemistry Letters (2002), 12 (20), 2815-2819CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)To investigate structure-activity relationships of the 9,10-acetal-9β-dihydro taxoids, we modified the 7-hydroxyl groups of the 9,10-acetonide-3'-(4-pyridyl) analog to deoxy, methoxy, α-F, and 7β,8β-methano group. As a result of this study, the 7-deoxy analog was found to be the strongest among these analogs. In addn., the 7-deoxy-3'-(4-pyridyl) and 7-deoxy-3'-(2-pyridyl) analogs showed stronger activity against cell lines expressing P-glycoprotein than the corresponding 3'-Ph analog.(c) Takeda, Y.; Yoshino, T.; Uoto, K.; Chiba, J.; Ishiyama, T.; Iwahana, M.; Jimbo, T.; Tanaka, N.; Terasawa, H.; Soga, T. New highly active taxoids from 9β-dihydrobaccatin-9,10-acetals. Part 3. Bioorg. Med. Chem. Lett. 2003, 13, 185– 190, DOI: 10.1016/S0960-894X(02)00891-0[Crossref], [PubMed], [CAS], Google Scholar.88chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XpsVels7s%253D&md5=a6f14a4695cb5dec9ece549610bcf5e5New highly active taxoids from 9β-dihydrobaccatin-9,10-acetals. Part 3Takeda, Yasuyuki; Yoshino, Toshiharu; Uoto, Kouichi; Chiba, Jun; Ishiyama, Takashi; Iwahana, Michio; Jimbo, Takeshi; Tanaka, Noriko; Terasawa, Hirofumi; Soga, TsunehikoBioorganic & Medicinal Chemistry Letters (2003), 13 (2), 185-190CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)We synthesized novel water-sol. and orally active taxane analogs, 7-deoxy-9β-dihydro-9,10-O-acetal taxanes. Cytotoxicities of the synthetic compds. were greater than those of paclitaxel and docetaxel, esp. against resistant cancer cell lines expressing P-glycoprotein. In addn., some compds., e.g. I, showed potent antitumor effects against B16 melanoma BL6 in vivo by both iv and po administration.(d) Takeda, Y.; Uoto, K.; Iwahana, M.; Jimbo, T.; Nagata, M.; Atsumi, R.; Ono, C.; Tanaka, N.; Terasawa, H.; Soga, T. New highly active taxoids from 9β-dihydrobaccatin-9,10-acetals. Part 5. Bioorg. Med. Chem. Lett. 2004, 14, 3209– 3215, DOI: 10.1016/j.bmcl.2004.03.109[Crossref], [PubMed], [CAS], Google Scholar.88dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXktVert7w%253D&md5=101061b2722bc9783756ba7761b5df69New highly active taxoids from 9β-dihydrobaccatin-9,10-acetals. Part 5Takeda, Yasuyuki; Uoto, Kouichi; Iwahana, Michio; Jimbo, Takeshi; Nagata, Motoko; Atsumi, Ryo; Ono, Chiho; Tanaka, Noriko; Terasawa, Hirofumi; Soga, TsunehikoBioorganic & Medicinal Chemistry Letters (2004), 14 (12), 3209-3215CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science B.V.)To improve the metabolic stability of I, which exhibited both in vitro antitumor activity and in vivo efficacy by both iv and po administration, we designed and synthesized new taxane analogs. Most of the synthetic compds. maintained excellent antitumor activity and were scarcely metabolized by human liver microsomes. And some compds. exhibited potent antitumor effects against B16 melanoma BL6 in vivo by both iv and po administration similarly to I.(e) Takeda, Y.; Uoto, K.; Chiba, J.; Horiuchi, T.; Iwahana, M.; Atsumi, R.; Ono, C.; Terasawa, H.; Soga, T. New highly active taxoids from 9β-dihydrobaccatin-9,10-acetals. Part 4. Bioorg. Med. Chem. 2003, 11, 4431– 4447, DOI: 10.1016/S0968-0896(03)00454-1[Crossref], [PubMed], [CAS], Google Scholar.88ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXnt1yis74%253D&md5=8e3712c84b388a750d9b52f51791ef59New highly active taxoids from 9β-Dihydrobaccatin-9,10-acetals. Part 4Takeda, Yasuyuki; Uoto, Kouichi; Chiba, Jun; Horiuchi, Takao; Iwahana, Michio; Atsumi, Ryo; Ono, Chiho; Terasawa, Hirofumi; Soga, TsunehikoBioorganic & Medicinal Chemistry (2003), 11 (20), 4431-4447CODEN: BMECEP; ISSN:0968-0896. (Elsevier Science Ltd.)It was shown that a new taxane analog I (R = H), which exhibited both in vitro antitumor activity and in vivo efficacy by both iv and po administration, was prone to be metabolized by human liver microsomes. We identified a major metabolite, M-1, generated by human liver microsomes as I (R = OH), a hydroxylated compd. at the pyridine ring of I (R = H). To improve the metabolic stability of I (R = H) , we designed and synthesized new taxane analogs, I (R = Me, Et, Cl, F, CF3, OMe) based on the structure of M-1, and obtained some compds. that maintained excellent antitumor activity and were scarcely metabolized by human liver microsomes.(f) Shionoya, M.; Jimbo, T.; Kitagawa, M.; Soga, T.; Tohgo, A. DJ-927, a novel oral taxane, overcomes P-glycoprotein-mediated multidrug resistance in vitro and in vivo. Cancer Sci. 2003, 94, 459– 466, DOI: 10.1111/j.1349-7006.2003.tb01465.x[Crossref], [PubMed], [CAS], Google Scholar.88fhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXls1WrtLY%253D&md5=c602b630e10e65548b9d00f326c020e6DJ-927, a novel oral taxane, overcomes P-glycoprotein-mediated multidrug resistance in vitro and in vivoShionoya, Motoko; Jimbo, Takeshi; Kitagawa, Mayumi; Soga, Tsunehiko; Tohgo, AkikoCancer Science (2003), 94 (5), 459-466CODEN: CSACCM; ISSN:1347-9032. (Japanese Cancer Association)DJ-927 is a novel taxane, which was selected for high soly., non-neurotoxicity, oral bioavailability, and potent antitumor activity. In this study, we compared the in vitro and in vivo efficacy of DJ-927 with those of paclitaxel and docetaxel. DJ-927 exhibited stronger cytotoxicity than paclitaxel and docetaxel in various tumor cell lines, esp. against P-glycoprotein (P-gp)-expressing cells. The cytotoxicity of DJ-927, unlike those of other taxanes, was not affected by the P-gp expression level in tumor cells, or by the co-presence of a P-gp modulator. When intracellular accumulation of the three compds. was compared, intracellular amts. of DJ-927 were much higher than those of paclitaxel or docetaxel, particularly in P-gp-pos. cells. In vivo, DJ-927 showed potent antitumor effects against two human solid tumors in male BALB/c-nu/nu mice, and yielded significant life-prolongation in a murine liver metastasis model with male C57BL/6 mice, in which neither paclitaxel nor docetaxel was effective. The results demonstrate the superior efficacy of orally administered DJ-927 over i.v. administered paclitaxel or docetaxel against P-gp-expressing tumors, probably due to higher intracellular accumulation. A phase I clin. trials of DJ-927 is currently ongoing in the US.(g) Ono, C.; Takao, A.; Atsumi, R. Absorption, distribution, and excretion of DJ-927, a novel orally effective taxane, in mice, dogs, and monkeys. Biol. Pharm. Bull. 2004, 27, 345– 351, DOI: 10.1248/bpb.27.345[Crossref], [PubMed], [CAS], Google Scholar.88ghttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXis1aluro%253D&md5=9f794b1d9eb68b4c85106dc589990ec1Absorption, distribution, and excretion of DJ-927, a novel orally effective taxane, in mice, dogs, and monkeysOno, Chiho; Takao, Atsushi; Atsumi, RyoBiological & Pharmaceutical Bulletin (2004), 27 (3), 345-351CODEN: BPBLEO; ISSN:0918-6158. (Pharmaceutical Society of Japan)DJ-927, currently undergoing Phase I clin. trial, is a new orally effective taxane with potent antitumor effects. The absorption, tissue distribution, and excretion of DJ-927 were investigated in mice, dogs, and monkeys after a single oral administration. After oral administration of [14C]DJ-927, radioactivity was rapidly absorbed, with the Cmax occurring within 1-2 h in all species. The blood and plasma radioactivity elimination was biphasic and species-dependent. Elimination half-life of plasma in dogs was much longer than those in monkeys or mice. In mice, radioactivity was rapidly distributed to all tissues except for the central nervous system, esp. to adrenal glands, liver, pituitary glands, kidneys, lungs, and spleen. In all species, radioactivity was mainly excreted in feces. Following a single oral administration to mice, more than 80% of the radioactivity was excreted within 48 h; in dogs and monkeys, 80% of the radioactivity was excreted within 168 h. Urinary excretion was less than 7% of radioactive dose in all species. In vitro plasma protein binding of [14C]DJ-927 in the mouse, dog, and monkey plasma ranged from 92-98%. These studies showed that, the novel oral taxane DJ-927 was rapidly absorbed in all three species when administered by the oral route. The long biol. half-life and slow elimination of radioactivity were distinctive in particular, compared with com. taxanes. DJ-927 (as parent compd. and its metabolites) is widely distributed to tissues except the brain. These preclin. data are useful for the design of clin. trials of DJ-927 and also for their interpretation.(h) Roche, M.; Kyriakou, H.; Seiden, M. Drug evaluation: tesetaxel - an oral semisynthetic taxane derivative. Curr. Opin. Investig. Drugs 2006, 7, 1092– 1099[CAS], Google Scholar.88hhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXntF2nug%253D%253D&md5=b14abcfadad23ba0278835891741da79Drug evaluation: tesetaxel - an oral semisynthetic taxane derivativeRoche, Maria; Kyriakou, Helena; Seiden, MichaelCurrent Opinion in Investigational Drugs (Thomson Scientific) (2006), 7 (12), 1092-1099CODEN: COIDAZ; ISSN:1472-4472. (Thomson Scientific)A review. Daiichi Sankyo Co Ltd (formerly Daiichi Seiyaku Co Ltd) was developing the oral semisynthetic taxane deriv. tesetaxel for the potential treatment of cancer, including colorectal and gastric cancer. However, despite early signs of promise, in Nov. 2006 tesetaxel was removed from Daiichi's development pipeline for failure to show clear benefit over existing, currently marketed agents for cancer chemotherapy.(i) Baas, P.; Szczesna, A.; Albert, I.; Milanowski, J.; Juhasz, E.; Sztancsik, Z.; von Pawel, J.; Oyama, R.; Burgers, S. Phase I/II study of a 3 weekly oral taxane (DJ-927) in patients with recurrent, advanced non-small cell lung cancer. J. Thorac. Oncol. 2008, 3, 745– 750, DOI: 10.1097/JTO.0b013e31817c73ff[Crossref], [PubMed], [CAS], Google Scholar.88ihttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1cvisFemtA%253D%253D&md5=4ea3ea49273bb406aa94fe93696b31ddPhase I/II study of a 3 weekly oral taxane (DJ-927) in patients with recurrent, advanced non-small cell lung cancerBaas Paul; Szczesna A; Albert I; Milanowski J; Juhasz E; Sztancsik Z; von Pawel J; Oyama R; Burgers SJournal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer (2008), 3 (7), 745-50 ISSN:.INTRODUCTION: A phase I/II study was performed to assess the efficacy and toxicity of a new oral taxane in patients with recurrent, advanced Non-small Cell Lung Cancer. PATIENTS AND METHODS: Patients who were treated with one prior, taxane free chemotherapy regimen, were eligible for this study. A single oral dose of DJ-927 (27 mg/m) was given every 3 weeks. In case of good tolerance, one dose escalation to 35 mg/m was allowed. Response and toxicity were measured and plasma pharmacokinetic analysis was performed during the first course. RESULTS: From October 2004 to September 2005, 36 patients gave informed consent and 34 received medication. The mean age was 58 years (range, 33-75 years). The majority of patients were pretreated with a combination of cisplatin and gemcitabine. Median interval between end of first treatment and the registration of this study was 7 months (range, 0.8-22 months). Twelve patients died on study of which eight due to disease progression. In four patients with preexisting cardiac disease, toxicity led to cardiac worsening and subsequent death. Grade 3 and 4 toxicities according to the National Cancer Institute Common Toxicity Criteria were neutropenia in 18 patients (53%), anemia in six patients (18%), nausea and fatigue in two patients (6%), febrile neutropenia and neurotoxicity in one patient (3%). The overall response rate for all patients was 5.6% (Confidence Interval [CI] 0.7-18.7%). The percentage of patients with stabilization for >6 weeks was 47%. The median time to progression was 97 days (CI: 47-167 days) and the median survival time was 120 days (CI: 68-222 days) for the ITT group. Since only a minority of patients (3) tolerated the higher drug dose we omitted this dose level because of hematological toxicity. Pharmacokinetic analysis showed that the median area under the curve (t = 0-168 hours) was 1752 +/- 1355 ngr/ml/h and the half-life was 167 +/- 77 hours. CONCLUSION: When administered once every 3 weeks, this oral taxane formulation of DJ-927 was well-absorbed with a long terminal half-life of 167 +/- 77 hour. DJ-927 has antitumor activity against Non-small Cell Lung Cancer when given as second-line monotherapy (overall response rate in 5.6%; CI 0.7-18.7%). Ten patients experienced SD for more than 8 weeks. Different types of dose administration (metronomic dosing) or combination with other cytotoxic agents should be considered in future studies.(j) Al Idrus, A. Odonate abandons breast cancer chemo drug, closes its doors. https://www.fiercebiotech.com/biotech/odonate-abandons-breast-cancer-chemo-drug-closes-its-doors (accessed March 22, 2021).
- 89(a) Sakya, S. M.; Bertinato, P.; Pratt, B.; Suarez-Contreras, M.; Lundy, K. M.; Minich, M. L.; Cheng, H.; Ziegler, C. B.; Kamicker, B. J.; Hayashi, S. F.; Santoro, S. L.; George, D. W.; Bertsche, C. D. Azalide 3,6-ketals: antibacterial activity and structure-activity relationships of aryl and hetero aryl substituted analogues. Bioorg. Med. Chem. Lett. 2003, 13, 1373– 1375, DOI: 10.1016/S0960-894X(03)00100-8[Crossref], [PubMed], [CAS], Google Scholar.89ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXitlKjsbg%253D&md5=fafa8fa9a3c71eeeadafccadcfc39e90Azalide 3,6-Ketals: antibacterial activity and structure-Activity relationships of aryl and hetero aryl substituted analoguesSakya, Subas M.; Bertinato, Peter; Pratt, Bryan; Suarez-Contreras, Melani; Lundy, Kristin M.; Minich, Martha L.; Cheng, Hengmiao; Ziegler, Carl B.; Kamicker, Barbara J.; Hayashi, Shigeru F.; Santoro, Sheryl L.; George, David M.; Bertsche, Camilla D.Bioorganic & Medicinal Chemistry Letters (2003), 13 (7), 1373-1375CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science B.V.)Aryl and hetero aryl substituted 3,6-ketals of 15-membered azalide analogs were synthesized and were found to have potent in vitro antibacterial activity against veterinary pathogens, including Staphylococcus aureus and Pasteurella multocida.(b) Cheng, H.; Dirlam, J. P.; Ziegler, C. B.; Lundy, K. M.; Hayashi, S. F.; Kamicker, B. J.; Dutra, J. K.; Daniel, K. L.; Santoro, S. L.; George, D. M.; Bertsche, C. D.; Sakya, S. M.; Suarez-Contreras, M. Synthesis and SAR of azalide 3,6-ketal aromatic derivatives as potent Gram-positive and Gram-negative antibacterial agents. Bioorg. Med. Chem. Lett. 2002, 12, 2431– 2434, DOI: 10.1016/S0960-894X(02)00434-1[Crossref], [PubMed], [CAS], Google Scholar89bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XlvVGjuro%253D&md5=93dd0e36ee3a4283a9ee6e2e4c9f88d4Synthesis and SAR of azalide 3,6-ketal aromatic derivatives as potent gram-positive and gram-negative antibacterial agentsCheng, Hengmiao; Dirlam, John P.; Ziegler, Carl B.; Lundy, Kristin M.; Hayashi, Shigeru F.; Kamicker, Barbara J.; Dutra, Jason K.; Daniel, Kirsten L.; Santoro, Sheryl L.; George, David M.; Bertsche, Camilla D.; Sakya, Subas M.; Suarez-Contreras, MelaniBioorganic & Medicinal Chemistry Letters (2002), 12 (17), 2431-2434CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)3,6-Ketals of 15-membered azalide pseudoaglycones are a novel series of macrolide antibiotics. The arom. derivs. of the azalide 3,6-ketals demonstrated potent antibacterial activities against both Gram-pos. and Gram-neg. bacteria.
- 90Wu, Y.-J. Highlights of semi-synthetic developments from erythromycin A. Curr. Pharm. Des. 2000, 6, 181– 223, DOI: 10.2174/1381612003401316[Crossref], [PubMed], [CAS], Google Scholar90https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXhslWqsbc%253D&md5=e7d1d4a8af661440dece5604b0dd8a62Highlights of semi-synthetic developments from erythromycin AWu, Yong-JinCurrent Pharmaceutical Design (2000), 6 (2), 181-223CODEN: CPDEFP; ISSN:1381-6128. (Bentham Science Publishers)A review with 88 refs. Earlier semi-synthetic studies of erythromycin A culminated in the discovery of two successful second generation macrolide antibiotics, azithromycin and clarithromycin, for the treatment of community-acquired bacterial infections. More recent structural modifications of erythromycin A have resulted in the discovery of novel ketolide antibiotics and new motilide pro-kinetic agents. This review is an account of the semi-synthetic developments from erythromycin A by chem. transformations.
- 91(a) Luke, D. R.; Foulds, G. Disposition of oral azithromycin in humans. Clin. Pharmacol. Ther. 1997, 61, 641– 648, DOI: 10.1016/S0009-9236(97)90098-9[Crossref], [PubMed], [CAS], Google Scholar.91ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXkslalt7s%253D&md5=78bfa904ec3721bafc0978b2203f3e59Disposition of oral azithromycin in humansLuke, David R.; Foulds, GeorgeClinical Pharmacology and Therapeutics (St. Louis) (1997), 61 (6), 641-648CODEN: CLPTAT; ISSN:0009-9236. (Mosby-Year Book)The oral bioavailability of azithromycin is approx. 37% in healthy subjects; little is known about the disposition of the remaining 63% of the dose. This study attempted to describe the fate of azithromycin before absorption. Twelve subjects with ileostomies in place for >1 mo were studied in this open-label, randomized, three-center, two-period, two-treatment crossover study. Subjects randomly received a single 500 mg i.v. infusion (over 1 h) or two 250 mg oral capsules after a fast for >12 h. Blood and ileostomy samples were collected serially after each administration and analyzed for azithromycin and two metabolites (descladinose and 9a-N-desmethyl metabolites) by HPLC with electrochem. detection. Mean ± SD peak concn. values after oral and i.v. administration were 0.21 ± 0.08 and 3.40 ± 1.12 μg/mL. Mean values for area under the serum concn. vs. time curve were 1.27 ± 0.65 and 7.14 ± 1.34 μg · hr/mL, resp. The abs. bioavailability of 16.2% was approx. one-half the value obsd. previously in healthy subjects. Recovery in ileostomy fluid (percent of dose in 24 h) of azithromycin, descladinose, and 9a-N-desmethyl metabolites were 13%, 0.5%, and 1% (total, 15%) after i.v. dosing and 47%, 13%, and 2% (total, 62%) after oral dosing. Total and ileal clearances were 776 ± 126 and 158 ± 63 mL/min after i.v. dosing. Because more descladinose metabolite was detected after oral dosing, acid degrdn. of azithromycin before absorption contributed to some loss in oral bioavailability. Further, ileal clearance (biliary plus intestinal excretion clearance) in this population represented 21% of total clearance. Taken together, these data suggest that the cause of low oral bioavailability of azithromycin is the result of incomplete absorption rather than acid degrdn. or extensive first-pass metab.(b) Lode, H.; Borner, K.; Koeppe, P.; Schaberg, T. Azithromycin-review of key chemical, pharmacokinetic and microbiological features. J. Antimicrob. Chemother. 1996, 37, 1– 8, DOI: 10.1093/jac/37.suppl_C.1[Crossref], [PubMed], [CAS], Google Scholar.91bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XktlOit7o%253D&md5=d174b2fde0dc0f51c5140b445dcbe5f0Azithromycin - review of key chemical, Pharmacokinetic and microbiological featuresLode, H.; Borner, K.; Koeppe, P.; Schaberg, T.Journal of Antimicrobial Chemotherapy (1996), 37 (Suppl. C, Azithromycin: Further Clinical Experience), 1-8CODEN: JACHDX; ISSN:0305-7453. (Saunders)A review with 40 refs. One of the chem. features that distinguishes the 15-membered ring azalide azithromycin from the 14-membered ring macrolide compd. erythromycin is the former's increased stability at acid pH. Azithromycin also differs pharmacokinetically from erythromycin, and important feature being azithromycin's ability to achieve high tissue concns., with the agent being delivered to the sites of infection by direct uptake and by targeted delivery via phagocytes. High tissue concns. are maintained for prolonged periods because of azithromycin's long half-life, leading to once-daily dosing for 3 or 5 days. Notable microbiol. features of azithromycin are in-vitro activity against many pyogenic bacteria (e.g. Neisseria gonorrhoeae and Moraxella catarrhalis), as well as organisms against which β-lactam antibiotics are usually ineffective (e.g. Legionella and Chlamydia spp.), organisms that are resistant to benzylpenicillin and erythromycin (e.g. Haemophilus influenzae) and organisms for which satisfactory therapy is limited (e.g. Toxoplasma gondii and the Mycobacterium avium-intracellulare complex). These properties of azithromycin suggest that it might be a useful agent for the treatment of a wide range of bacterial infections.(c) Allin, D.; James, I.; Zachariah, J.; Carr, W.; Cullen, S.; Middleton, A.; Newson, P.; Lytle, T.; Coles, S. Comparison of once- and twice-daily clarithromycin in the treatment of adults with severe acute lower respiratory tract infections. Clin. Ther. 2001, 23, 1958– 1968, DOI: 10.1016/S0149-2918(01)80149-1[Crossref], [PubMed], [CAS], Google Scholar91chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XhtVyltLs%253D&md5=cf7296e8b1787c4d817c6b8de25992e1Comparison of once- and twice-daily clarithromycin in the treatment of adults with severe acute lower respiratory tract infectionsAllin, Dennis; James, Ian; Zachariah, Jollye; Carr, William; Cullen, Stephen; Middleton, Alan; Newson, Penny; Lytle, Thomas; Coles, StephenClinical Therapeutics (2001), 23 (12), 1958-1968CODEN: CLTHDG; ISSN:0149-2918. (Excerpta Medica, Inc.)Although the modified-release (MR) formulation of clarithromycin has demonstrated bioequivalence to the immediate-release (IR) formulation and thus can be prescribed for lower respiratory tract infections (LRTIs), a MEDLINE search from 1995 through 1998 and information on file with the manufacturer indicate that no data are available on the effectiveness of this new formulation in the treatment of severe LRTIs such as community-acquired pneumonia. This study was designed to compare clin. success rates (percentage of patients with clin. cure or improvement) with once- and twice-daily regimens of clarithromycin in the treatment of patients with severe, acute LRTIs requiring oral antibiotic therapy. In this multicenter, investigator-blinded, randomized, parallel-group study, adult patients with clin. evidence suggesting severe, acute LRTI were recruited from 22 general practices in the United Kingdom. Patients were randomly allocated to receive either clarithromycin 500 mg BID (IR tablets) or clarithromycin 1 g OD (two 500-mg MR tablets) for 7 to 14 days. The outcome measures were resoln. of or improvement in clin. signs and symptoms (including resoln. of cough), unscheduled visits for the same symptom, days to resumption of normal activities, and improvements in quality of life (assessed using the EQ-5D version of the EuroQoL questionnaire). Clin., microbiol., and serol. assessments were performed before, during, and after treatment. Efficacy and safety data were analyzed on an intent-to-treat basis. One hundred sixty men (n = 83) and women (n = 77) between the ages of 19 and 88 yr took part in the study, 78 receiving clarithromycin 500 mg BID and 82 receiving clarithromycin 1 g OD. At 4 wk after the start of treatment, the high clin. success rates were comparable between groups: 84.6% with clarithromycin 500 mg BID and 90.2% with clarithromycin 1 g OD. No significant differences in outcome measures were noted between the 2 regimens. Both treatments were well tolerated, with taste disturbance being the most commonly reported adverse event (10.6% vs. 6.1% with clarithromycin 500 mg BID and 1 g OD, resp.). The 2 clarithromycin regimens were equally efficacious and well tolerated in the treatment of severe, acute LRTIs. However, caution should be exercised in applying these results to the general population, because the study excluded certain categories of patients who would normally be treated. In addn., the small sample size may have obscured clin. significant differences between the 2 regimens.
- 92Botelho, A. F. M.; Pierezan, F.; Soto-Blanco, B.; Melo, M. M. A review of cardiac glycosides: structure, toxicokinetics, clinical signs, diagnosis and antineoplastic potential. Toxicon 2019, 158, 63– 68, DOI: 10.1016/j.toxicon.2018.11.429[Crossref], [PubMed], [CAS], Google Scholar92https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisVOjsrjL&md5=5e326c61b99905489fde9268ea6a18c4A review of cardiac glycosides: Structure, toxicokinetics, clinical signs, diagnosis and antineoplastic potentialBotelho, Ana Flavia M.; Pierezan, Felipe; Soto-Blanco, Benito; Melo, Marilia MartinsToxicon (2019), 158 (), 63-68CODEN: TOXIA6; ISSN:0041-0101. (Elsevier Ltd.)Cardiac glycosides (CGs) are secondary compds. found in plants and amphibians and are widely distributed in nature with potential cardiovascular action. Their mechanism is based on the blockage of the heart's sodium potassium ATPase, with a pos. inotropic effect. Some of the most well-known CGs are digoxin, ouabain, oleandrin, and bufalin. They have similar chem. structures: a lactone ring, steroid ring, and sugar moiety. Digoxin, ouabain, and oleandrin are classified as cardenolides, consisting of a lactone ring with five carbons, while bufalin is classified as bufodienolides, with a six-carbon ring. Small structural differences det. variations in the toxicokinetics and toxicodynamics of such substances. Most case reports of poisoning caused by CGs are assocd. with cardiovascular toxicity, causing a variety of arrhythmias and lesions in the heart tissue. Exptl. studies also describe important similarities among different CGs, esp. regarding species sensitivity. Recent studies furthermore focus on their antineoplastic potential, with controversial results. Data from research studies and case reports were reviewed to identify the main characteristics of the CGs, including toxicokinetics, toxicodynamics, clin. signs, electrocardiog., pathol. findings, antineoplastic potential and the main techniques used for diagnostic purposes.
- 93(a) Cohen, A.; Kroon, R.; Schoemaker, H.; Breimer, D.; Vliet-Verbeek, A.; Brandenburg, H. The bioavailability of digoxin from three oral formulations measured by a specific HPLC assay. Br. J. Clin. Pharmacol. 1993, 35, 136– 142, DOI: 10.1111/j.1365-2125.1993.tb05679.x[Crossref], [PubMed], [CAS], Google Scholar.93ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3sXitF2ltro%253D&md5=9179871c552baf9c603b9c715f90ac49The bioavailability of digoxin from three oral formulations measured by a specific HPLC assayCohen, A. F.; Kroon, R.; Schoemaker, H. C.; Breimer, D. D.; Van Vliet-Verbeek, A.; Brandenburg, H. C.British Journal of Clinical Pharmacology (1993), 35 (2), 136-42CODEN: BCPHBM; ISSN:0306-5251.The abs. bioavailability of three oral formulations of digoxin, 1.0 mg, was studied in 12 young healthy volunteers in a four way randomized cross-over study using an i.v. control. Digoxin tablets (250 μg), liq.-filled digoxin capsules (100 μg) and an exptl. enteric-coated capsule (100 μg) were evaluated. In vitro dissoln. at pH 1 demonstrated extensive hydrolytic breakdown of digoxin from the tablets and capsules but not from the enteric-coated capsules. Serum digoxin concns. were measured by fluorescence polarization immunoassay (FPI). The systemic availability of the capsules was 70.5%, and that of the tablets 71.5%. Drug was less available from the enteric-coated capsules (62.1%) measured with FPI. These results were reflected in the urinary drug recoveries measured by FPI. By contrast, there were no differences in urinary recovery of unchanged digoxin between any of the oral treatments, when this was measured by HPLC. The cross-reactivity of immunoassays for metabolites of digoxin may produce artifactual results and the optimal pharmaceutical formulation for digoxin remains to be detd.(b) Peters, U.; Falk, L. C.; Kalman, S. M. Digoxin metabolism in patients. Arch. Intern. Med. 1978, 138, 1074– 1076, DOI: 10.1001/archinte.1978.03630320018009[Crossref], [PubMed], [CAS], Google Scholar93bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaE1c3gvFOltg%253D%253D&md5=84140f281d5a4e2e2dc0fbdd12918645Digoxin metabolism in patientsPeters U; Falk L C; Kalman S MArchives of internal medicine (1978), 138 (7), 1074-6 ISSN:0003-9926.In 100 patients receiving digoxin to control heart disease, metabolic reduction of the lactone ring of digoxin was investigated. An average of 12.4% +/- 11% (range 2.2% to 52%) of the lipid-extractable cardenolides in a 24-hour urine sample contained the reduced lactone ring. Fifty-three excreted more than 10% while seven excreted more than 35% of these metabolic products. Reduction was not influenced by age, sex, dose, or blood level of digoxin. One patient who excreted 52% reduced products in the urine had 40% reduced digoxin-metabolites in the blood; the main metabolite was dihydrodigoxin. We found no influence of other drug therapy or concurrent disease on reduction of digoxin in this group.
- 94(a) Cowie, M. R.; Fisher, M. SGLT2 inhibitors: mechanisms of cardiovascular benefit beyond glycaemic control. Nat. Rev. Cardiol. 2020, 17, 761– 772, DOI: 10.1038/s41569-020-0406-8[Crossref], [PubMed], [CAS], Google Scholar.94ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtlynu7jL&md5=d3d6908db59d4e0a05e62071e53c3b45SGLT2 inhibitors: mechanisms of cardiovascular benefit beyond glycaemic controlCowie, Martin R.; Fisher, MilesNature Reviews Cardiology (2020), 17 (12), 761-772CODEN: NRCAE6; ISSN:1759-5002. (Nature Research)A Review. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are effective antidiabetic therapies in patients with type 2 diabetes mellitus and are assocd. with improved glycemic control as well as with redns. in body mass and blood pressure. In large cardiovascular outcome trials in patients with diabetes, SGLT2 inhibitors improve cardiovascular and renal outcomes, including hospitalization for heart failure, with this benefit extending to patients without diabetes who have heart failure with reduced ejection fraction. Early natriuresis with a redn. in plasma vol., a consequent rise in haematocrit, improved vascular function, a redn. in blood pressure and changes in tissue sodium handling are all likely to have a role. Addnl. mechanisms of SGLT2 inhibitors that might be beneficial include a redn. in adipose tissue-mediated inflammation and pro-inflammatory cytokine prodn., a shift towards ketone bodies as the metabolic substrate for the heart and kidneys, reduced oxidative stress, lowered serum uric acid level, reduced glomerular hyperfiltration and albuminuria, and suppression of advanced glycation end-product signalling. Further outcome trials and mechanistic studies, including in patients with heart failure with preserved ejection fraction or non-diabetic kidney disease, might identify other possible mechanisms of benefit of SGLT2-inhibitor therapy.(b) Moradi-Marjaneh, R.; Paseban, M.; Sahebkar, A. Natural products with SGLT2 inhibitory activity: possibilities of application for the treatment of diabetes. Phytother. Res. 2019, 33, 2518– 2530, DOI: 10.1002/ptr.6421[Crossref], [PubMed], [CAS], Google Scholar.94bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvFOis73N&md5=06b598d553e6844213e517a3d862588fNatural products with SGLT2 inhibitory activity: Possibilities of application for the treatment of diabetesMoradi-Marjaneh, Reyhaneh; Paseban, Maryam; Sahebkar, AmirhosseinPhytotherapy Research (2019), 33 (10), 2518-2530CODEN: PHYREH; ISSN:0951-418X. (John Wiley & Sons Ltd.)A review. Diabetes mellitus currently affects as many as 400 million people worldwide, creating a heavy economic burden and stretching health care resources. A dysfunction of glucose homeostasis underlies the disease. Despite advances in the treatment of diabetes, many patients still suffer from complications and side effects; hence, development of more effective treatments for diabetes is still desirable. SGLT2 is the principle cotransporter involved in glucose reabsorption in the kidney. SGLT2 inhibition reduces glucose reabsorption by the kidney and ameliorates plasma glucose concn. The interest in natural products that can be used for the inhibition of SGLT2 is growing. The flavonoid phlorizin, which can be isolated from the bark of apple trees, has been used as lead structure due to its inhibitory activity of SGLT1 and SGLT2. Some phlorizin-derived synthetic compds., including canagliflozin, dapagliflozin, empagliflozin, ipragliflozin, and ertugliflozin, are approved by the food and drug administration to treat type 2 diabetes mellitus (T2DM), whereas others are under clin. trials investigation. In addn., other natural product-derived compds. have been investigated for their ability to improve blood glucose control. The present review summarizes the natural products with SGLT2 inhibitory activity, and the synthetic compds. obtained from them, and discusses their application for the treatment of diabetes.(c) Mariadoss, A. V. A.; Vinyagam, R.; Rajamanickam, V.; Sankaran, V.; Venkatesan, S.; David, E. Pharmacological aspects and potential use of phloretin: a systemic review. Mini-Rev. Med. Chem. 2019, 19, 1060– 1067, DOI: 10.2174/1389557519666190311154425[Crossref], [PubMed], [CAS], Google Scholar94chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhslWrsb7K&md5=b07eeb707f93ddc5f31c17f021705755Pharmacological Aspects and Potential Use of Phloretin: A Systemic ReviewMariadoss, Arokia V. A.; Vinyagam, Ramachandran; Rajamanickam, Vinothkumar; Sankaran, Vijayalakshmi; Venkatesan, Sathish; David, ErnestMini-Reviews in Medicinal Chemistry (2019), 19 (13), 1060-1067CODEN: MMCIAE; ISSN:1389-5575. (Bentham Science Publishers Ltd.)A review. Over the past two decades, many researchers have concluded that a diet rich in polyphenolic compds. plays an important therapeutic role in reducing the risk of cancer, cardiovascular disease, inflammation, diabetes, and other degenerative diseases. Polyphenolic compds. have been reported to be involved in neutralization of reactive oxygen species and charged radicals, and have anticarcinogenic effects, hepatoprotective effects, low-glycemic response, and other benefits. The benefits of fruits and vegetables may be partly attributable to polyphenolic compds., which have antioxidant and free radical scavenging properties. Fruits such as apples contain a variety of phytochems., including (+)-catechin and (-)-epicatechin, phlorizin, phloretin quercetin, cyanidin-3-Ogalactoside, chlorogenic acid, and p-coumaric acid, all of which are strong antioxidants. Phloretin, a natural phenolic compd., is a dihydrochalcone, which is present in the apple. It exhibits a wide variety of activities such as antioxidative, anti-inflammatory, anti-microbial, anti-allergic, anticarcinogenic, anti-thrombotic, and hepatoprotective, besides being involved in the activation of apoptotic assocd. gene expression and signal transduction in mol. pathways. Despite a multitude of clin. studies, new efforts are needed in clin. research to det. the complete therapeutic potential of phloretin.
- 95Tsujihara, K.; Hongu, M.; Saito, K.; Kawanishi, H.; Kuriyama, K.; Matsumoto, M.; Oku, A.; Ueta, K.; Tsuda, M.; Saito, A. Na+-glucose cotransporter (SGLT) inhibitors as antidiabetic agents. 4. Synthesis and pharmacological properties of 4′-dehydroxyphlorizin derivatives substituted on the B ring. J. Med. Chem. 1999, 42, 5311– 5324, DOI: 10.1021/jm990175n[ACS Full Text], [CAS], Google Scholar95https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXnslSltbc%253D&md5=429449e4687602cac7866ef1bf279790Na+-Glucose Cotransporter (SGLT) Inhibitors as Antidiabetic Agents. 4. Synthesis and Pharmacological Properties of 4'-Dehydroxyphlorizin Derivatives Substituted on the B RingTsujihara, Kenji; Hongu, Mitsuya; Saito, Kunio; Kawanishi, Hiroyuki; Kuriyama, Kayoko; Matsumoto, Mamoru; Oku, Akira; Ueta, Kiichiro; Tsuda, Minoru; Saito, AkiraJournal of Medicinal Chemistry (1999), 42 (26), 5311-5324CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)In the authors' studies of Na+-glucose cotransporter (SGLT) inhibitors as antidiabetic agents, a series of novel 4'-dehydroxyphlorizin derivs. substituted on the B ring was prepd. and their effects on urinary glucose excretion were evaluated in rats. Introduction of only a small alkyl group at the 4'-position increased the activity, and 3-(benzo[b]furan-5-yl)-2',6'-dihydroxy-4'-methylpropiophenone 2'-O-β-D-glucopyranoside I (R = H) showed the most potent effect. To overcome hydrolysis by β-glucosidase in the digestive tract, the OH groups on the glucose moiety of I (R = H) were modified. Three prodrugs were more potent than the parent compd. by oral administration, and finally 3-(benzo[b]furan-5-yl)-2',6'-dihydroxy-4'-methylpropiophenone 2'-O-(6-O-methoxycarbonyl-β-D-glucopyranoside) I (R = CO2Me) was selected as a new promising candidate. This compd. was metabolized mainly by liver esterase to the active form, I (R = H) which was about 10 times more potent in inhibiting SGLT. In oral glucose tolerance test in db/db mice, I (R = CO2Me) dose-dependently suppressed the elevation of glucose levels. Single administration reduced hyperglycemia concurrently with increase of glucose excretion into urine in diabetic KK-Ay mice. Furthermore, I (R = CO2Me) suppressed the elevation of blood glucose levels but did not lower it below the normal level even in fasted conditions in KK-Ay mice. Addnl., long-term treatment dose-dependently reduced hyperglycemia and HbA1c in KK-Ay mice. These pharmacol. data strongly suggest that I (R = CO2Me) has a therapeutic potential in the treatment of NIDDM.
- 96Kees, K. L.; Fitzgerald, J. J., Jr.; Steiner, K. E.; Mattes, J. F.; Mihan, B.; Tosi, T.; Mondoro, D.; McCaleb, M. L. New potent antihyperglycemic agents in db/db mice: synthesis and structure-activity relationship studies of (4-substituted benzyl) (trifluoromethyl)pyrazoles and -pyrazolones. J. Med. Chem. 1996, 39, 3920– 3928, DOI: 10.1021/jm960444z[ACS Full Text], [CAS], Google Scholar96https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XlsVCisb8%253D&md5=76973cdadbffa8553a6c3bfd29116f79New Potent Antihyperglycemic Agents in db/db Mice: Synthesis and Structure-Activity Relationship Studies of (4-Substituted benzyl)(trifluoromethyl)pyrazoles and -pyrazolonesKees, Kenneth L.; Fitzgerald, John J., Jr.; Steiner, Kurt E.; Mattes, James F.; Mihan, Brenda; Tosi, Theresa; Mondoro, Diane; McCaleb, Michael L.Journal of Medicinal Chemistry (1996), 39 (20), 3920-3928CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The synthesis, structure-activity relation (SAR) studies, and antidiabetic characterization of 1,2-dihydro-4-[[4-(methylthio)phenyl]methyl]-5-(trifluoromethyl)-3H-pyrazol-3-one (as the hydroxy tautomer; WAY-123783, 4) are described. Substitution of 4-methylthio, methylsulfinyl, or Et to a benzyl group at C4, in combination with trifluoromethyl at C5 of pyrazol-3-one, generated potent antihyperglycemic agents in obese, diabetic db/db mice (16-30% redn. in plasma glucose at 2 mg/kg). The antihyperglycemic effect was assocd. with a robust glucosuria (>8 g/dL) obsd. in nondiabetic mice. Chem. trapping of four of the seven possible tautomeric forms of the heterocycle by mono- and dialkylation at the acidic hydrogens provided several addnl. potent analogs (39-43% redn. at 5 mg/kg) of the lead 4 as well as a dialkylated pair of regioisomers that showed sepn. of the assocd. glucosuric effect produced by all of the active analogs in normal mice. Further pharmacol. characterization of the lead WAY-123783 (ED50 = 9.85 mg/kg, po in db/db mice), in oral and s.c. glucose tolerance tests, indicated that unlike the renal and intestinal glucose absorption inhibitor phlorizin, pyrazolone 4 does not effectively block intestinal glucose absorption. SAR and addnl. pharmacol. data reported herein suggest that WAY-123783 represents a new class of potent antihyperglycemic agents which correct hyperglycemia by selective inhibition of renal tubular glucose resorption.
- 97(a) Washburn, W. N. Development of the renal glucose reabsorption inhibitors: a new mechanism for the pharmacotherapy of diabetes mellitus type 2. J. Med. Chem. 2009, 52, 1785– 1794, DOI: 10.1021/jm8013019[ACS Full Text.], [CAS], Google Scholar97ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXisVCjtbg%253D&md5=3ca641223da08b46057465fa2228f900Development of the Renal Glucose Reabsorption Inhibitors: A New Mechanism for the Pharmacotherapy of Diabetes Mellitus Type 2Washburn, William N.Journal of Medicinal Chemistry (2009), 52 (7), 1785-1794CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review.(b) Choi, C.-I. Sodium-glucose cotransporter 2 (SGLT2) inhibitors from natural products: discovery of next-generation antihyperglycemic agents. Molecules 2016, 21, 1136, DOI: 10.3390/molecules21091136[Crossref], [CAS], Google Scholar97bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslKis7rO&md5=68a60f0c2c669cf328bf9a123491f6c6Sodium-glucose cotransporter 2 (SGLT2) inhibitors from natural products: discovery of next-generation antihyperglycemic agentsChoi, Chang-IkMolecules (2016), 21 (9), 1136/1-1136/12CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)Diabetes mellitus is a chronic condition assocd. with the metabolic impairment of insulin actions, leading to the development of life-threatening complications. Although many kinds of oral antihyperglycemic agents with different therapeutic mechanisms have been marketed, their undesirable adverse effects, such as hypoglycemia, wt. gain, and hepato-renal toxicity, have increased demand for the discovery of novel, safer antidiabetic drugs. Since the important roles of the sodium-glucose cotransporter 2 (SGLT2) for glucose homeostasis in the kidney were recently elucidated, pharmacol. inhibition of SGLT2 has been considered a promising therapeutic target for the treatment of type 2 diabetes. Since the discovery of the first natural SGLT2 inhibitor, phlorizin, several synthetic glucoside analogs have been developed and introduced into the market. Furthermore, many efforts to find new active constituents with SGLT2 inhibition from natural products are still ongoing. This review introduces the history of research on the development of early-generation SGLT2 inhibitors, and recent progress on the discovery of novel candidates for SGLT2 inhibitor from several natural products that are widely used in traditional herbal medicine.
- 98(a) Shimizu, K.; Fujikura, H.; Fushimi, N.; Nishimura, T.; Tatani, K.; Katsuno, K.; Fujimori, Y.; Watanabe, S.; Hiratochi, M.; Nakabayashi, T.; Kamada, N.; Arakawa, K.; Hikawa, H.; Azumaya, I.; Isaji, M. Discovery of remogliflozin etabonate: A potent and highly selective SGLT2 inhibitor. Bioorg. Med. Chem. 2021, 34, 116033, DOI: 10.1016/j.bmc.2021.116033[Crossref], [PubMed], [CAS], Google Scholar.98ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXjvFOhtLs%253D&md5=849d17482f1d8b025c6c72b0d230808bDiscovery of remogliflozin etabonate: A potent and highly selective SGLT2 inhibitorShimizu, Kazuo; Fujikura, Hideki; Fushimi, Nobuhiko; Nishimura, Toshihiro; Tatani, Kazuya; Katsuno, Kenji; Fujimori, Yoshikazu; Watanabe, Shinjiro; Hiratochi, Masahiro; Nakabayashi, Takeshi; Kamada, Noboru; Arakawa, Koichi; Hikawa, Hidemasa; Azumaya, Isao; Isaji, MasayukiBioorganic & Medicinal Chemistry (2021), 34 (), 116033CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)We optimized the structure of an active metabolite (1) of WAY-123783, which was obtained from mouse urine after oral administration, to improve selectivity for SGLT2 and oral bioavailability. O-glucoside deriv. 24 (remogliflozin etabonate) was subsequently identified as a potent, highly selective, and orally available SGLT2 inhibitor.(b) Sigafoos, J. F.; Bowers, G. D.; Castellino, S.; Culp, A. G.; Wagner, D. S.; Reese, M. J.; Humphreys, J. E.; Hussey, E. K.; O’Connor Semmes, R. L.; Kapur, A.; Tao, W.; Dobbins, R. L.; Polli, J. Assessment of the drug interaction risk for remogliflozin etabonate, a sodium-dependent glucose cotransporter-2 inhibitor: evidence from in vitro, human mass balance, and ketoconazole interaction studies. Drug Metab. Dispos. 2012, 40, 2090– 2101, DOI: 10.1124/dmd.112.047258[Crossref], [PubMed], [CAS], Google Scholar.98bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsFKkt73L&md5=e416fe362dec69d516bc6dee55988d92Assessment of the drug interaction risk for remogliflozin etabonate, a sodium-dependent glucose cotransporter-2 inhibitor: evidence from in vitro, human mass balance, and ketoconazole interaction studiesSigafoos, James F.; Bowers, Gary D.; Castellino, Stephen; Culp, Amanda G.; Wagner, David S.; Reese, Melinda J.; Humphreys, Joan E.; Hussey, Elizabeth K.; Semmes, Robin L. O'Connor; Kapur, Anita; Tao, Wenli; Dobbins, Robert L.; Polli, Joseph W.Drug Metabolism & Disposition (2012), 40 (11), 2090-2101CODEN: DMDSAI; ISSN:1521-009X. (American Society for Pharmacology and Experimental Therapeutics)Remogliflozin etabonate is the ester prodrug of remogliflozin, a selective sodium-dependent glucose cotransporter-2 inhibitor. This work investigated the absorption, metab., and excretion of [14C]remogliflozin etabonate in humans, as well as the influence of P-glycoprotein (Pgp) and cytochrome P 450 (P 450) enzymes on the disposition of remogliflozin etabonate and its metabolites to understand the risks for drug interactions. After a single oral 402 ± 1.0 mg (106 ± 0.3 μCi) dose, [14C]remogliflozin etabonate is rapidly absorbed and extensively metabolized. The area under the concn.-time curve from 0 to infinity [AUC(0-∞)] of plasma radioactivity was approx. 14-fold higher than the sum of the AUC(0-∞) of remogliflozin etabonate, remogliflozin, and 5-methyl-4-({4-[(1-methylethyl)oxy]phenyl}methyl)-1H-pyrazol-3-yl-β-D-glucopyranoside (GSK279782), a pharmacol. active N-dealkylated metabolite. Elimination half-lives of total radioactivity, remogliflozin etabonate, and remogliflozin were 6.57, 0.39, and 1.57 h, resp. Products of remogliflozin etabonate metab. are eliminated primarily via renal excretion, with 92.8% of the dose recovered in the urine. Three glucuronide metabolites made up the majority of the radioactivity in plasma and represent 67.1% of the dose in urine, with 5-methyl-1-(1-methylethyl)-4-({4-[(1-methylethyl)oxy]phenyl}methyl)-1H-pyrazol-3-yl-β-D-glucopyranosiduronic acid (GSK1997711) representing 47.8% of the dose. In vitro studies demonstrated that remogliflozin etabonate and remogliflozin are Pgp substrates, and that CYP3A4 can form GSK279782 directly from remogliflozin. A ketoconazole clin. drug interaction study, along with the human mass balance findings, confirmed that CYP3A4 contributes less than 50% to remogliflozin metab., demonstrating that other enzyme pathways (e.g., P450s, UDP-glucuronosyltransferases, and glucosidases) make significant contributions to the drug's clearance. Overall, these studies support a low clin. drug interaction risk for remogliflozin etabonate due to the availability of multiple biotransformation pathways.(c) Kapur, A.; O’Connor-Semmes, R.; Hussey, E. K.; Dobbins, R. L.; Tao, W.; Hompesch, M.; Smith, G. A.; Polli, J. W.; James, C. D. Jr.; Mikoshiba, I.; Nunez, D. J. First human dose-escalation study with remogliflozin etabonate, a selective inhibitor of the sodium-glucose transporter 2 (SGLT2), in healthy subjects and in subjects with type 2 diabetes mellitus. BMC Pharmacol. Toxicol. 2013, 14, 26, DOI: 10.1186/2050-6511-14-26[Crossref], [PubMed], [CAS], Google Scholar98chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtFCntL3N&md5=b604de376b31602bf111b4b82ad9a7eeFirst human dose-escalation study with remogliflozin etabonate, a selective inhibitor of the sodium-glucose transporter 2 (SGLT2), in healthy subjects and in subjects with type 2 diabetes mellitusKapur, Anita; O'Connor-Semmes, Robin; Hussey, Elizabeth K.; Dobbins, Robert L.; Tao, Wenli; Hompesch, Marcus; Smith, Glenn A.; Polli, Joseph W.; James, Charles D., Jr.; Mikoshiba, Imao; Nunez, Derek J.BMC Pharmacology and Toxicology (2013), 14 (), 26CODEN: BPTMAB; ISSN:2050-6511. (BioMed Central Ltd.)Background: Remogliflozin etabonate (RE) is the prodrug of remogliflozin, a selective inhibitor of the renal sodium dependent glucose transporter 2 (SGLT2), which could increase urine glucose excretion (UGE) and lower plasma glucose in humans. Methods: This double blind, randomized, placebo controlled, single dose, dose escalation, crossover study is the first human trial designed to evaluate safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of RE. All subjects received single oral doses of either RE or placebo sepd. by approx. 2 wk intervals. In Part A, 10 healthy subjects participated in 5 dosing periods where they received RE (20 mg, 50 mg, 150 mg, 500 mg or 1000 mg) or placebo (4:1 active to placebo ratio per treatment period). In Part B, 6 subjects with type 2 diabetes mellitus (T2DM) participated in 3 dose periods where they received RE (50 mg and 500 mg) or placebo (2:1 active to placebo per treatment period). The study protocol was registered with the NIH clin. trials data base with identifier NCT01571661. Results: RE was generally well tolerated; there were no serious adverse events. In both populations, RE was rapidly absorbed and converted to remogliflozin (time to max. plasma concn. [Cmax;Tmax] approx. 1 h). Generally, exposure to remogliflozin was proportional to the administered dose. RE was rapidly eliminated (mean T1/2 of ∼25 min; mean plasma T1/2 for remogliflozin was 120 min) and was independent of dose. All subjects showed dose dependent increases in 24-h UGE, which plateaued at approx. 200 to 250 mmol glucose with RE doses ≥150 mg. In T2DM subjects, increased plasma glucose following OGTT was attenuated by RE in a drug dependent fashion, but there were no clear trends in plasma insulin. There were no apparent effects of treatment on plasma or urine electrolytes. Conclusions: The results support progression of RE as a potential treatment for T2DM.
- 99(a) Mohan, V.; Mithal, A.; Joshi, S. R.; Aravind, S. R.; Chowdhury, S. Remogliflozin etabonate in the treatment of type 2 diabetes: design, development, and place in therapy. Drug Des., Dev. Ther. 2020, 14, 2487– 2501, DOI: 10.2147/DDDT.S221093[Crossref], [PubMed], [CAS], Google Scholar.99ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXisFalsbrL&md5=95d0cff5e02f9a4c5743b4f9b0081e55Remogliflozin etabonate in the treatment of type 2 diabetes: design, development, and place in therapyMohan, Viswanathan; Mithal, Ambrish; Joshi, Shashank R.; Aravind, S. R.; Chowdhury, SubhankarDrug Design, Development and Therapy (2020), 14 (), 2487-2501CODEN: DDDTAQ; ISSN:1177-8881. (Dove Medical Press Ltd.)Type 2 diabetes mellitus (T2DM) is an emerging epidemic in Asian countries, esp. in India. With the advent of the SGLT2 inhibitor class of drugs demonstrating benefits beyond glycemic control, viz. wt. loss, blood pressure redn., and cardiovascular and renal protection, the management of T2DM has taken a quantum leap. Remogliflozin etabonate (RE) is the latest addn. to the SGLT2 inhibitor class of drugs that have been recently approved in India for the management of T2DM. RE is a potent and selective inhibitor of SGLT2 with the unique distinction of being administered as a prodrug, existence of active metabolites, and short half-life necessitating twice-daily dosing. The Phase III study of RE demonstrated it to be an efficacious and safe agent and non-inferior to the currently available SGLT2 inhibitors. This paper reviews not only the pharmacokinetics, pharmacodynamics, clin. efficacy, and safety profile of RE but also its mol. and clin. development program. This review has taken into consideration all available published as well as unpublished literature on RE and discusses the individual studies performed during its development for characterization of pharmacol. profile.(b) Markham, A. Remogliflozin etabonate: first global approval. Drugs 2019, 79, 1157– 1161, DOI: 10.1007/s40265-019-01150-9[Crossref], [PubMed], [CAS], Google Scholar99bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtFyisrjP&md5=d599b50ff2c1d3131e7d3dbbc2ce663fRemogliflozin Etabonate: First Global ApprovalMarkham, AnthonyDrugs (2019), 79 (10), 1157-1161CODEN: DRUGAY; ISSN:0012-6667. (Springer International Publishing AG)A review. Remogliflozin, a selective sodium-glucose co-transporter subtype 2 (SGLT2) inhibitor, which is to be administered as remogliflozin etabonate (Remo, Remozen), the prodrug for remogliflozin, recently received its first approval as a treatment for type 2 diabetes mellitus (T2DM) in India. This article summarizes the milestones in the development of remogliflozin etabonate leading to this first approval for T2DM.
- 100Ting, H. J.; Murad, J. P.; Espinosa, E. V. P.; Khasawneh, F. T. Thromboxane A2 receptor: biology and function of a peculiar receptor that remains resistant for therapeutic targeting. J. Cardiovasc. Pharmacol. Ther. 2012, 17, 248– 259, DOI: 10.1177/1074248411424145[Crossref], [PubMed], [CAS], Google Scholar100https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtlCqtLjO&md5=461dd114846130ee068e7be9005c235fThromboxane A2 receptor: biology and function of a peculiar receptor that remains resistant for therapeutic targetingTing, Harold J.; Murad, John P.; Espinosa, Enma V. P.; Khasawneh, Fadi T.Journal of Cardiovascular Pharmacology and Therapeutics (2012), 17 (3), 248-259CODEN: JCPTFE; ISSN:1074-2484. (Sage Publications)A review. While blood platelets express several G-protein-coupled receptors (GPCRs) that play pivotal roles in their activation, several diseases, for example thrombotic disorders, may develop if these receptors are inappropriately activated. Thus, these receptors have been the subject of investigations to design therapeutic interventions for managing multiple thrombosis-based disease states. One such GPCR, the thromboxane A2 receptor (TPR), remains resistant to such interventions. The present review provides a crit. examn. of the binding, structural biol., and signaling of TPRs. The review also provides a rationale for using principles of "drug rediscovery" as an alternative/viable approach for the therapeutic targeting of TPRs. To this end, it is noteworthy that many US Food and Drug Administration (FDA)-approved drugs have been found to selectively (and nonselectively) block TPR-mediated functional responses, for example platelet aggregation, as described in this review. Therefore, while none of the antagonists, thus far developed for targeting TPRs, have made it into clin. use, this peculiar receptor can be antagonized by a large no. of drugs used for indications unrelated to thrombosis.
- 101(a) Fried, J.; John, V.; Szwedo, M. J., Jr.; Chen, C.; O’Yang, C.; Morinelli, T. A.; Okwu, A. K.; Halushka, P. V. Synthesis of 10,10-difluorothromboxane A2, a potent and chemically stable thromboxane agonist. J. Am. Chem. Soc. 1989, 111, 4510– 4511, DOI: 10.1021/ja00194a062[ACS Full Text.], [CAS], Google Scholar101ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1MXkslOlurg%253D&md5=d7e0d48fabf0168ed2452a0f97a21b09Synthesis of 10,10-difluorothromboxane A2, a potent and chemically stable thromboxane agonistFried, Josef; John, Varghese; Szwedo, Mitchell J., Jr.; Chen, Chien Kuang; O'Yang, Counde; Morinelli, Thomas A.; Okwu, Anselm K.; Halushka, Perry V.Journal of the American Chemical Society (1989), 111 (12), 4510-11CODEN: JACSAT; ISSN:0002-7863.The total synthesis of 10,10-difluorothromboxane A2 (I), the first stable analog of thromboxane A2 (TXA2) possessing the dioxa[3.1.1]bicycloheptane nucleus, and of three stereoisomers is described. The starting material is the racemic dibenzyl ether II (R = CH2Ph) which contains the 7,7-difluoro-2,6-dioxa[3.1.1]bicycloheptane system previously shown to undergo hydrolytic cleavage of the oxetane ring at 10-8 times the rate of TXA2 (R. Noyori et al. 1984). The key reaction in this synthesis is the regio- and enantiospecific enzymic hydrolysis of II (R = Ac) to the (+)-monoacetate, which was converted to the target compds. without hydrolytic cleavage of the oxetane ring during any one of the synthetic steps. I stimulated platelet aggregation and contraction of saphenous veins at potencies similar to those of TXA2. The three stereoisomeric compds. were receptor antagonists in platelets but were agonists in saphenous veins, indicating two types of thromboxane receptors.(b) Morinelli, T. A.; Okwu, A. K.; Mais, D. E.; Halushka, P. V.; John, V.; Chen, C. K.; Fried, J. Difluorothromboxane A2 and stereoisomers: stable derivatives of thromboxane A2 with differential effects on platelets and blood vessels. Proc. Natl. Acad. Sci. U. S. A. 1989, 86, 5600– 5604, DOI: 10.1073/pnas.86.14.5600[Crossref], [PubMed], [CAS], Google Scholar.101bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1MXlt1Oiu78%253D&md5=b4661df86a2fa237f549265a2a1e5bd5Difluorothromboxane A2 and stereoisomers: stable derivatives of thromboxane A2 with differential effects on platelets and blood vesselsMorinelli, Thomas A.; Okwu, Anselm K.; Mais, Dale E.; Halushka, Perry V.; John, Varghese; Chen, Chien Kuang; Fried, JosefProceedings of the National Academy of Sciences of the United States of America (1989), 86 (14), 5600-4CODEN: PNASA6; ISSN:0027-8424.The selective effects on human platelets and canine saphenous veins of 4 stable difluorinated TXA2 analogs and TXA2 in which the characteristic 2,6-dioxa[3.1.1]bicycloheptane structure of TXA2 has been retained was studied. The 4 compds. differ in the stereochem. of the 5,6 double bond and(or) the 15-hydroxyl group. Only 10,10-difluoro-TXA2 (I) with the natural stereochem. of TXA2 was an agonist in both platelets and canine saphenous veins (EC50 = 36 nM and 3.7 nM, resp.)9. (15R)-10,10-Difluoro-TXA2 (II), (5E)-10,10-difluoro-TXA2 (III), and (5E,15R)-10,10-difluoro-TXA2 (IV) were antagonists of platelet aggregation stimulated by compd. I (Kd = 98, 140, and 1450 nM, resp.). However, II, III, and IV stimulated contraction of canine saphenous veins (EC50 = 36, 31, and 321 nM, resp.). All 4 compds. displaced the TXA2/PGH2 antagonist 9,11-dimethylmethano-11,12-methano-16-(3-125I-4-hydroxyphenyl)-13,14-dihydro-13-aza-15αβ-ω-tetranor-TXA2 from its platelet receptor (Kd values = 100 nM, I; 280 nM, II; 230 nM, III; and 1410 nM, IV). These results support the existence of 2 subtypes of TXA2/PGH2 receptors and emphasize the importance of the stereochem. requirements of these TXA2 analogs for interaction with these receptors. These stable fluorinated TXA2 analogs should prove useful tools for the further characterization of these and other TXA2/PGH2 receptors.(c) Jing, C.; Mallah, S.; Kriemen, E.; Bennett, S. H.; Fasano, V.; Lennox, A. J.; Hers, I.; Aggarwal, V. K. Synthesis, stability, and biological studies of fluorinated analogues of thromboxane A2. ACS Cent. Sci. 2020, 6, 995– 1000, DOI: 10.1021/acscentsci.0c00310[ACS Full Text.], [CAS], Google Scholar101chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtFWjsLjO&md5=bab9b0261524b2585dd6a724ec9208aeSynthesis, Stability, and Biological Studies of Fluorinated Analogues of Thromboxane A2Jing, Changcheng; Mallah, Shahida; Kriemen, Ella; Bennett, Steven H.; Fasano, Valerio; Lennox, Alastair J. J.; Hers, Ingeborg; Aggarwal, Varinder K.ACS Central Science (2020), 6 (6), 995-1000CODEN: ACSCII; ISSN:2374-7951. (American Chemical Society)Platelet activation results in the generation of thromboxane A2 (TxA2), which promotes thrombus formation by further amplifying platelet function, as well as causing vasoconstriction. Due to its role in thrombus formation and cardiovascular disease, its prodn. is the target of antiplatelet drugs such as aspirin. However, the study of TxA2-stimulated cellular function has been limited by its instability (t1/2 = 32 s, pH = 7.4). Although more stable analogs such as U46619 and difluorinated 10,10-F2-TxA2 have been prepd., we targeted a closer mimic to TxA2 itself, monofluorinated 10-F-TxA2, since the no. of fluorine atoms can affect function. Key steps in the synthesis of F-TxA2 included α-fluorination of a lactone bearing a β-alkoxy group, and a novel synthesis of the strained acetal. F-TxA2 was found to be 105 more stable than TxA2, and surprisingly was only slightly less stable than F2-TxA2. Preliminary biol. studies showed that F-TxA2 has similar potency as TxA2 toward inducing platelet aggregation but was superior to F2-TxA2 in activating integrin αIIbβ3. The synthesis is described of 10-F-thromboxane A2 I, a stable mimic of TxA2 (105 x more stable) with similar potency as TxA2 toward inducing platelet aggregation.(d) Schaaf, T. R.; Bussolotti, D. L.; Parry, M. J.; Corey, E. J. Synthesis of 11a,9a-epoxymethanothromboxane A2: a stable, optically active TxA2 agonist. J. Am. Chem. Soc. 1981, 103, 6502– 6505, DOI: 10.1021/ja00411a044[ACS Full Text], [CAS], Google Scholar101dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL3MXlvFOhsLg%253D&md5=a3a1c37ecc21aa5519009c5f58d3c192Synthesis of 11α,9α-epoxymethanothromboxane A2: a stable, optically active TxA2 agonistSchaaf, Thomas K.; Bussolotti, Donald L.; Parry, M. John; Corey, E. J.Journal of the American Chemical Society (1981), 103 (21), 6502-5CODEN: JACSAT; ISSN:0002-7863.11α,9α-Epoxymethanothromboxane A2 (I) [79440-53-2], a chem. stable, chiral homolog of thromboxane A2 (TxA2), and II [79440-72-5] were synthesized and tested pharmacol. The synthesis of I involved the formal stereoselective insertion of a methylene unit into the lactone of chiral III [62158-33-2], acid catalyzed formation of the bridged THF moiety and elaboration of the side chains. Initial pharmacol. evaluation indicates that I inhibits TxA2 agonist activity in rabbit platelet rich plasma and on the isolated rabbit aorta, is devoid of antagonist effects in these systems, and is without appreciable thromboxane synthetase inhibiting activity.
- 102(a) Longridge, J. L.; Nicholson, S. The alkaline stability of (5Z)-7-([2RS,4RS,5SR]-4-o-hydroxyphenyl-2-trifluoromethyl-1,3-dioxan-5-yl)hept-5-enoic acid, ICI 185282. A remarkable intramolecular hydride transfer from a trifluoromethyl substituted carbon atom. J. Chem. Soc., Perkin Trans. 2 1990, 965– 970, DOI: 10.1039/p29900000965[Crossref], [CAS], Google Scholar.102ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3cXlslWhsbY%253D&md5=689f8f75ca9d4049da56914d6c8a829dThe alkaline stability of (5Z)-7-([2RS,4RS,5SR]-4-(o-hydroxyphenyl)-2-(trifluoromethyl)-1,3-dioxan-5-yl)hept-5-enoic acid, ICI 185282. A remarkable intramolecular hydride transfer from a trifluoromethyl substituted carbon atomLongridge, Jethro L.; Nicholson, StuartJournal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999) (1990), (6), 965-70CODEN: JCPKBH; ISSN:0300-9580.The kinetics of hydrolysis of (5Z)-7-([2RS,4RS,5SR]-2-trifluoromethyl-1,3-dioxan-5-yl)hept-5-enoic acid, ICI 185282, have been studied. At low pH the compd. undergoes conventional acid-catalyzed hydrolysis of the dioxane ring. However, under alk. conditions, a second reaction is obsd. Studies by NMR show that this process involves a quite unexpected intramol. hydride transfer from a carbon atom carrying a strongly electron-withdrawing trifluoromethyl substituent. Addnl. studies on closely related compds. are reported and a mechanism involving a ring-opened quinone methide intermediate is proposed.(b) Brewster, A. G.; Brown, G. R.; Foubister, A. J.; Jessup, R.; Smithers, M. J. The synthesis of a novel thromboxane receptor antagonist 4(Z)-6-(2-o-chlorophenyl-4-o-hydroxyphenyl-1,3-dioxan-cis-5-yl) hexenoic acid ICI 192605. Prostaglandins 1988, 36, 173– 178, DOI: 10.1016/0090-6980(88)90304-8[Crossref], [PubMed], [CAS], Google Scholar102bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1MXltVY%253D&md5=04aef2317af13fda6b3549eeed195307The synthesis of a novel thromboxane receptor antagonist 4(Z)-6-(2-0-chlorophenyl-4-0-hydroxyphenyl-1,3-dioxan-cis-5-yl)hexenoic acid, ICI 192605Brewster, A. G.; Brown, G. R.; Foubister, A. J.; Jessup, R.; Smithers, M. J.Prostaglandins (1988), 36 (2), 173-8CODEN: PRGLBA; ISSN:0090-6980.The title compd. (I) was prepd. and its pharmacol. as a thromboxane receptor antagonist were studied in humans and lab. animals in vivo and in vitro.
- 103(a) O’Neill, P. M.; Posner, G. H. A medicinal chemistry perspective on artemisinin and related endoperoxides. J. Med. Chem. 2004, 47, 2945– 2964, DOI: 10.1021/jm030571c[ACS Full Text.], [CAS], Google Scholar103ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXjvVSgsrc%253D&md5=d39dbc04bfb86ab753bbe96d52411070A Medicinal Chemistry Perspective on Artemisinin and Related EndoperoxidesO'Neill, Paul M.; Posner, Gary H.Journal of Medicinal Chemistry (2004), 47 (12), 2945-2964CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review on aspects of the chem., mechanism of action, metab., and toxicity of the endoperoxide class of antimalarial drugs with a focus on lead compds. (semisynthetic and synthetic) that have emerged as potential next-generation analogs. The authors also briefly cover artemisinin combination therapy (ACT) of malaria and discuss the potential of drug hybrids and prodrugs as new approaches to delivering combination chemotherapy through a sing.(b) Krishna, S.; Bustamante, L.; Haynes, T. K.; Staines, H. M. Artemisinins: their growing importance in medicine. Trends Pharmacol. Sci. 2008, 29, 520– 527, DOI: 10.1016/j.tips.2008.07.004[Crossref], [PubMed], [CAS], Google Scholar103bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtFOmurjL&md5=a074709688abde63c63e67f14c6cdab5Artemisinins: their growing importance in medicineKrishna, Sanjeev; Bustamante, Leyla; Haynes, Richard K.; Staines, Henry M.Trends in Pharmacological Sciences (2008), 29 (10), 520-527CODEN: TPHSDY; ISSN:0165-6147. (Elsevier B.V.)A review. Artemisinins are derived from exts. of sweet wormwood (Artemisia annua) and are well established for the treatment of malaria, including highly drug-resistant strains. Their efficacy also extends to phylogenetically unrelated parasitic infections such as schistosomiasis. More recently, they have also shown potent and broad anticancer properties in cell lines and animal models. In this review, we discuss recent advances in defining the role of artemisinins in medicine, with particular focus on their controversial mechanisms of action. This safe and cheap drug class that saves lives at risk from malaria can also have important potential in oncol.
- 104(a) Ilett, K. F.; Ethell, B. T.; Maggs, J. L.; Davis, D. M. E.; Batty, K. T.; Burchell, B.; Binh, T. W.; Thu, L. T.; Hung, N. C.; Pirmohamed, M.; Park, B. K.; Edwards, G. Glucuronidation of dihydroartemisinin in vivo and by human liver microsomes and expressed UDP-glucuronosyltransferases. Drug Metab. Dispos. 2002, 30, 1005– 1012, DOI: 10.1124/dmd.30.9.1005[Crossref], [PubMed], [CAS], Google Scholar.104ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XmsVShurY%253D&md5=692a3619c62277bcdad8b113338d943bGlucuronidation of dihydroartemisinin in vivo and by human liver microsomes and expressed UDP-glucuronosyltransferasesIlett, Kenneth F.; Ethell, Brian T.; Maggs, James L.; Davis, Timothy M. E.; Batty, Kevin T.; Burchell, Brian; Binh, Tran Quang; Thu, Le Thi Anh; Hung, Nguyen Canh; Pirmohamed, Munir; Park, B. Kevin; Edwards, GeoffreyDrug Metabolism and Disposition (2002), 30 (9), 1005-1012CODEN: DMDSAI; ISSN:0090-9556. (American Society for Pharmacology and Experimental Therapeutics)This work studied the metabolic pathways of dihydroartemisinin (DHA), the active metabolite of the artemisinin deriv. artesunate (ARTS). Urine was collected from Vietnamese adults with falciparum malaria who had received 120 mg ARTS i.v., and metabolites were analyzed by HPLC-mass spectrometry (HPLC-MS). Human liver microsomes were also incubated with [12-3H]DHA and cofactors for either glucuronidation or cytochrome P 450-catalyzed oxidn. Human liver cytosol was incubated with a cofactor for sulfation. Metabolites were detected by HPLC-MS and/or HPLC with radiochem. detection. Metab. of DHA by recombinant human UDP-glucuronosyltransferases (UGTs) was studied. HPLC-MS anal. of urine identified α-DHA-β-glucuronide (α-DHA-G) and a product characterized as the THF isomer of α-DHA-G. DHA was present only in very small amts. The ratio of the THF isomer to α-DHA-G was highly variable (median 0.75; range 0.09-64). Nevertheless, α-DHA-G was generally the major urinary product of DHA glucuronidation in patients. The THF isomer appeared to be at least partly a product of nonenzymic reactions occurring in urine and was readily formed from α-DHA-G by iron-mediated isomerization. In human liver microsomal incubations, DHA-G (diastereomer unspecified) was the only metabolite found (Vmax 177 pmol/min/mg, Km 90 μM). α-DHA-G was formed in incubations of DHA with expressed UGT1A9 (Km 32 μM, Vmax 8.9 pmol/mg/min) or UGT2B7 (Km 438 μM, Vmax 10.9 pmol/mg/min) but not with UGT1A1 or UGT1A6. There was no significant metab. of DHA by cytochrome P 450 oxidn. or by cytosolic sulfotransferases. It is concluded that α-DHA-G is an important metabolite of DHA in humans and that its formation is catalyzed by UGT1A9 and UGT2B7.(b) O’Neill, P. M.; Scheinmann, F.; Stachulski, A. V.; Maggs, J. L.; Park, B. K. Efficient preparations of the α-glucuronides of dihydroartemisinin and structural confirmation of the human glucuronide metabolite. J. Med. Chem. 2001, 44, 1467– 1470, DOI: 10.1021/jm001061a[ACS Full Text], [CAS], Google Scholar104bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXislKju7s%253D&md5=8e83e257700e07fef45568475e78ae4fEfficient Preparations of the β-Glucuronides of Dihydroartemisinin and Structural Confirmation of the Human Glucuronide MetaboliteO'Neill, Paul M.; Scheinmann, Feodor; Stachulski, Andrew V.; Maggs, James L.; Park, B. KevinJournal of Medicinal Chemistry (2001), 44 (9), 1467-1470CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)New and greatly improved prepns. of the 12α,1'β- and 12β,1'β-glucuronides of dihydroartemisinin (DHA) are reported using anomeric hydroxy and imidate glucuronate intermediates. Comparison of the synthetic and natural materials shows that the human metabolite of DHA is the 12α-epimer.
- 105(a) Nga, T. T. T.; Menage, C.; Begue, J.-P.; Bonnet-Delpon, D.; Gantier, J.-C.; Pradines, B.; Doury, J.-C.; Thac, T. D. Synthesis and antimalarial activities of fluoroalkyl derivatives of dihydroartemisinin. J. Med. Chem. 1998, 41, 4101– 4108, DOI: 10.1021/jm9810147[ACS Full Text.], [CAS], Google Scholar105ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXlvFGitbg%253D&md5=687617ce7330b1e931a7b8f006886bfaSynthesis and Antimalarial Activities of Fluoroalkyl Derivatives of DihydroartemisininNga, Truong Thi Thanh; Menage, Celine; Begue, Jean-Pierre; Bonnet-Delpon, Daniele; Gantier, Jean-Charles; Pradines, Bruno; Doury, Jean-Claude; Thac, Truong DinhJournal of Medicinal Chemistry (1998), 41 (21), 4101-4108CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Fluoroalkyl ethers of dihydroartemisinin were prepd. via the reaction of fluoroalkyl alcs. with dihydroartemisinin using different methods (BF3,Et2O or TMSCl catalysis or Mitsunobu reaction). Ethers I (R = CF3, CF2CF3, CF2CF2CF3, CF2CHFCF3; R1 = R2 = H) derived from primary fluoroalkyl alcs. were obtained in moderate to good yields by these methods. Ethers I, e.g. (R =CF3, R1 = Ph, R2 = H; R=R1 = CF3, R2 = H; R=R1=R2 = C6H5) were prepd. from fluoroalkyl secondary and tertiary alcs. and phenol using the Mitsunobu reaction. In vitro antimalarial activities of ethers toward Plasmodium falciparum W-2 asiatic strain are moderate while in vivo activities against Plasmodium berghei (NT 173) were excellent.(b) Magueur, G.; Crousse, B.; Charneau, S.; Grellier, P.; Begue, J.-P.; Bonnet-Delpon, D. Fluoroartemisinin: trifluoromethyl analogues of artemether and artesunate. J. Med. Chem. 2004, 47, 2694– 2699, DOI: 10.1021/jm0310333[ACS Full Text.], [CAS], Google Scholar105bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXisl2it7o%253D&md5=8f35ed345b0011c56c6154ac7405800bFluoroartemisinin: Trifluoromethyl Analogues of Artemether and ArtesunateMagueur, Guillaume; Crousse, Benoit; Charneau, Sebastien; Grellier, Philippe; Begue, Jean-Pierre; Bonnet-Delpon, DanieleJournal of Medicinal Chemistry (2004), 47 (10), 2694-2699CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The synthesis of a series of C-10 trifluoromethyl ethers of artemisinin has been achieved from key bromide I, itself carried out in two steps from artemisinin. The substitution of I with methanol, ethanol, or succinic acid allowed the access of C-10 CF3 analogs of β-artemether, β-arteether, or artesunate, resp., in good yields (up to 89%). The presence of the CF3 group at C-10 of artemisinin clearly increased the chem. stability under simulated stomach acid conditions. For example, the CF3 analog of arteether was found to be around 45 times more stable than arteether itself. The influence of the CF3 moiety on biol. activity was also highlighted. CF3 analogs of artemether and arteether exhibited a high in vivo antimalarial activity on mice infected with Plasmodium berghei NK173, with a complete clearance of the parasitemia during the entire observation period (25 days).(c) Bgu, J.-P.; Bonnet-Delpon, D. Antimalarial fluoroartimisinins: increased metabolic and chemical stability. Fluorine in Medicinal Chemistry and Chemical Biology 2009, 141– 163, DOI: 10.1002/9781444312096.ch6 .(d) Njokah, M. J.; Kang’ethe, J. N.; Kinyua, J.; Kariuki, D.; Kimani, F. T. In vitro selection of Plasmodium falciparum Pfcrt and Pfmdr1 variants by artemisinin. Malar. J. 2016, 15, 381, DOI: 10.1186/s12936-016-1443-y[Crossref], [PubMed], [CAS], Google Scholar105dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhslarsr%252FI&md5=3dd5a8a4bdb05d82af33b6735bd45b4dIn vitro selection of Plasmodium falciparum Pfcrt and Pfmdr1 variants by artemisininNjokah, Muturi J.; Kang'ethe, Joseph N.; Kinyua, Johnson; Kariuki, Daniel; Kimani, Francis T.Malaria Journal (2016), 15 (), 381/1-381/9CODEN: MJAOAZ; ISSN:1475-2875. (BioMed Central Ltd.)Background: Anti-malarial drugs are the major focus in the prevention and treatment of malaria. Artemisinin-based combination therapy (ACT) is the WHO recommended first-line treatment for Plasmodium falciparum malaria across the endemic world. Also ACT is increasingly relied upon in treating Plasmodium vivax malaria where chloroquine is failing. The emergence of artemisinin drug-resistant parasites is a serious threat faced by global malaria control programs. Therefore, the success of treatment and intervention strategies is highly pegged on understanding the genetic basis of resistance. Methods: Here, resistance in P. falciparum was generated in vitro for artemisinin to produce levels above clin. relevant concns. in vivo, and the mol. haplotypes investigated. Genomic DNA was extd. using the QIAamp mini DNA kit. DNA sequences of Pfk13, Pfcrt and Pfmdr1 genes were amplified by PCR and the amplicons were successfully sequenced. Single nucleotide polymorphisms were traced by std. bidirectional sequencing and reading the transcripts against wild-type sequences in Codon code Aligner Version 5.1 and NCBI blast. Results: Exposure of parasite strains D6 and W2 to artemisinin resulted in a decrease in parasite susceptibility to artemisinin (W2 and D6) and lumefantrine (D6 only). The parasites exhibited elevated IC50s to multiple artemisinins, with >twofold resistance to artemisinin; however, the resistance index obtained with std. methods was noticeably less than expected for parasite lines recovered from 50 μg/mL 48 h drug pressure. The change in parasite susceptibility was assocd. with Pfmdr-185K mutation, a mutation never reported before. The Pfcrt-CVMNK genotype (Pfcrt codons 72-76) was retained and notably, the study did not detect any polymorphisms reported to reduce P. falciparum susceptibility in vivo in the coding sequences of the Pfk13 gene. Discussion: This data demonstrate that P. falciparum has the capacity to develop resistance to artemisinin derivs. in vitro and that this phenotype is achieved by mutations in Pfmdr1, the genetic changes that are also underpinning lumefantrine resistance. This finding is of practical importance, because artemisinin drugs in Kenya are used in combination with lumefantrine for the treatment of malaria. Conclusion: Artemisinin resistance phenotype as has been shown in this work, is a decrease in parasites susceptibility to artemisinin derivs. together with the parasite's ability to recover from drug-induced dormancy after exposure to drug dosage above the in vivo clin. concns. The study surmises that Pfmdr1 may play a role in the anti-malarial activity of artemisinin.
- 106Elkeles, R. Fibrates: old drugs with a new role in type 2 diabetes prevention?. Br. J. Diabetes Vasc. Dis. 2011, 11, 4– 9, DOI: 10.1177/1474651410397245
- 107Pirat, C.; Farce, A.; Lebegue, N.; Renault, N.; Furman, C.; Millet, R.; Yous, S.; Speca, S.; Berthelot, P.; Desreumaux, P.; Chavatte, P. Targeting peroxisome proliferator-activated receptors (PPARs): development of modulators. J. Med. Chem. 2012, 55, 4027– 4061, DOI: 10.1021/jm101360s[ACS Full Text], [CAS], Google Scholar107https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XpsVOruw%253D%253D&md5=f32ec6b6d9f353199a56345f8cfc475cTargeting Peroxisome Proliferator-Activated Receptors (PPARs): Development of ModulatorsPirat, Celine; Farce, Amaury; Lebegue, Nicolas; Renault, Nicolas; Furman, Christophe; Millet, Regis; Yous, Said; Speca, Silvia; Berthelot, Pascal; Desreumaux, Pierre; Chavatte, PhilippeJournal of Medicinal Chemistry (2012), 55 (9), 4027-4061CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)This review covers the rapid progress in the functional anal. of the Peroxisome Proliferator-Activated Receptors (PPARs), which has led to a greater understanding of these receptors and has established them as mol. targets for the development of drugs against metabolic diseases. Natural and synthetic ligands for the three subtypes PPARalpha, PPARgamma and PPARbeta/delta, are reported: agonists or antagonists, partial or selective PPARs modulators (SPPARMs), dual agonists and pan-PPARalpha,gamma,beta/delta agonists. We conclude with the future of PPARs ligands research and the emergence of new hybrid compds. of the multitarget drug genre with a particular interest in the treatment of chronic inflammation.
- 108(a) Asaki, T.; Aoki, T.; Hamamoto, T.; Sugiyama, Y.; Ohmachi, S.; Kuwabara, K.; Murakami, K.; Todo, M. Structure-activity studies on 1,3-dioxane-2-carboxylic acid derivatives, a novel class of subtype-selective peroxisome proliferator-activated receptor δ. (PPARα) agonists. Bioorg. Med. Chem. 2008, 16, 981– 994, DOI: 10.1016/j.bmc.2007.10.007[Crossref], [PubMed], [CAS], Google Scholar.108ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsF2jsrc%253D&md5=c774d3d4fff3c548faeb114dc1c2dc9bStructure-activity studies on 1,3-dioxane-2-carboxylic acid derivatives, a novel class of subtype-selective peroxisome proliferator-activated receptor α (PPARα) agonistsAsaki, Tetsuo; Aoki, Tomiyoshi; Hamamoto, Taisuke; Sugiyama, Yukiteru; Ohmachi, Shinji; Kuwabara, Kenji; Murakami, Kohji; Todo, MakotoBioorganic & Medicinal Chemistry (2008), 16 (2), 981-994CODEN: BMECEP; ISSN:0968-0896. (Elsevier Ltd.)A series of 1,3-dioxane carboxylic acid derivs. was synthesized and evaluated for human PPAR transactivation activity. Structure-activity relationships on the phenyloxazole moiety of the lead compd. I revealed that the introduction of small hydrophobic substituents at the 4-position of the terminal Ph ring increased the PPARα agonist activity, and that the oxazole heterocycle was essential to the maintenance of both potency and PPARα subtype-selectivity. This investigation led to the identification of highly potent and selective human PPARα agonists (II and III). In KK-Ay type 2 diabetic mice, these compds. significantly lowered plasma triglyceride and very-low-d. plus low-d. lipoprotein cholesterol levels while simultaneously raising HDL cholesterol levels. The results suggest that highly potent and subtype-selective PPARα agonists will be promising drugs for the treatment of metabolic disorders in type 2 diabetes.(b) Aoki, T.; Asaki, T.; Hamamoto, T.; Sugiyama, Y.; Ohmachi, S.; Kuwabara, K.; Murakami, K.; Todo, M. Discovery of a novel class of 1,3-dioxane-2-carboxylic acid derivatives as subtype-selective peroxisome proliferator-activated receptor δ (PPARα) agonists. Bioorg. Med. Chem. Lett. 2008, 18, 2128– 2132, DOI: 10.1016/j.bmcl.2008.01.086[Crossref], [PubMed], [CAS], Google Scholar108bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXjtlymu7w%253D&md5=b2947fecc4c870ad7449fbf1219dd856Discovery of a novel class of 1,3-dioxane-2-carboxylic acid derivatives as subtype-selective peroxisome proliferator-activated receptor α (PPARα) agonistsAoki, Tomiyoshi; Asaki, Tetsuo; Hamamoto, Taisuke; Sugiyama, Yukiteru; Ohmachi, Shinji; Kuwabara, Kenji; Murakami, Kohji; Todo, MakotoBioorganic & Medicinal Chemistry Letters (2008), 18 (6), 2128-2132CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)A series of 1,3-dioxane-2-carboxylic acid derivs. was synthesized and evaluated for agonist activity at human peroxisome proliferator-activated receptor (PPAR) subtypes. Structure-activity relationship studies led to the identification of compd. I as a potent PPARα agonist with high subtype selectivity at human receptor subtypes. This compd. exhibited a substantial hypolipidemic effect in type 2 diabetic KK-Ay mice.
- 109(a) Tschierske, C.; Kshler, H.; Zaschke, H.; Kleinpete, E. The anomeric effect of the carboethoxy group in oxygen and sulfur containing heterocycles. Tetrahedron 1989, 45, 6987– 6998, DOI: 10.1016/S0040-4020(01)89165-1[Crossref], [CAS], Google Scholar.109ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3cXitlCltbk%253D&md5=ce81459cc5ab840783c89752d7ffb4d5The anomeric effect of the carboethoxy group in oxygen and sulfur containing heterocyclesTschierske, C.; Koehler, H.; Zaschke, H.; Kleinpeter, E.Tetrahedron (1989), 45 (22), 6987-98CODEN: TETRAB; ISSN:0040-4020.The anomeric effect of the carboethoxy substituents and the ring oxygen in 1,3-dioxane- and 1,3-oxathiane-2-carboxylates has been estd. in low polar solvents by including empirical correlation factor α to be 4 kJ/mol. The conformational energies of the 2-carboethoxy substituent fit the parabolic Zefirov dependence on the solvent dielec. const. in the 1,3-dioxane-2-carboxylates. Deviations in the case of the 1,3-oxathiane-2-carboxylates indicate a second conformational equil. involved which is the rotation of the COOR substituent about the exocyclic bond to the heterocyclic ring. Preferred rotamers have been assigned and discussed in terms of special πCO/3d(S) orbital interactions.(b) Harabe, T.; Matsumoto, T.; Shioiri, T. Conformational analysis and selective hydrolysis of 2,5-disubstituted-1,3-dioxane-2-carboxylic acid esters. Tetrahedron Lett. 2007, 48, 1443– 1446, DOI: 10.1016/j.tetlet.2006.12.117[Crossref], [CAS], Google Scholar.109bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXht1ajtLc%253D&md5=49783bf4aad64b69935b6641666d71c4Conformational analysis and selective hydrolysis of 2,5-disubstituted-1,3-dioxane-2-carboxylic acid estersHarabe, Tetsuji; Matsumoto, Takatoshi; Shioiri, TakayukiTetrahedron Letters (2007), 48 (8), 1443-1446CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)5-Alkyl-2-methyl-2-carbomethoxy-1,3-dioxanes were found to have a cis preferential configuration in the equil. state, and the ester hydrolysis rate of the trans-isomers was faster than that of the cis-isomers. Conformational anal. and charge calcn. of the carbomethoxy group in both dioxanes elucidated this selectivity.(c) Harabe, T.; Matsumoto, T.; Shioiri, T. Esters of 2,5-multisubstituted-1,3-dioxane-2-carboxylic acid: their conformational analysis and selective hydrolysis. Tetrahedron 2009, 65, 4044– 4052, DOI: 10.1016/j.tet.2009.02.076[Crossref], [CAS], Google Scholar109chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXkslOqtb0%253D&md5=99f2b4cd44cd7148864d5bb7e9b496b5Esters of 2,5-multisubstituted-1,3-dioxane-2-carboxylic acid: their conformational analysis and selective hydrolysisHarabe, Tetsuji; Matsumoto, Takatoshi; Shioiri, TakayukiTetrahedron (2009), 65 (20), 4044-4052CODEN: TETRAB; ISSN:0040-4020. (Elsevier Ltd.)The carbomethoxy group at the C2 position of the 2,5-multisubstituted 1,3-dioxanes prefers the axial conformation rather than the equatorial one due to an anomeric effect. The trans isomers of the 5-monosubstituted compds. are more selectively hydrolyzed than the cis isomers. Based on the calcd. results, hydrolysis to the trans isomers is attributed to the larger carbonyl charges of the trans than those of the cis isomers. The anomeric and homoanomeric effects will explain the axial preference of the carbomethoxy group and selective hydrolysis to the trans isomers. Furthermore, the calcd. stability between the cis and trans isomers is in good agreement with the exptl. results in the equil. state.
- 110(a) Zaware, P.; Shah, S. R.; Pingali, H.; Makadia, P.; Thube, B.; Pola, S.; Patel, D.; Priyadarshini, P.; Suthar, D.; Shah, M.; Jamili, J.; Sairam, K. V.; Giri, S.; Patel, L.; Patel, H.; Sudani, H.; Patel, H.; Jain, M.; Patel, P.; Bahekar, R. Modulation of PPAR subtype selectivity. Part 2: Transforming PPARα/δ dual agonist into a selective PPAR agonist through bioisosteric modification. Bioorg. Med. Chem. Lett. 2011, 21, 628– 632, DOI: 10.1016/j.bmcl.2010.12.032[Crossref], [PubMed], [CAS], Google Scholar.110ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXktVKrtg%253D%253D&md5=82697a3e007c0ea5344cf68a1273f904Modulation of PPAR subtype selectivity. Part 2: Transforming PPARα/γ dual agonist into α selective PPAR agonist through bioisosteric modificationZaware, Pandurang; Shah, Shailesh R.; Pingali, Harikishore; Makadia, Pankaj; Thube, Baban; Pola, Suresh; Patel, Darshit; Priyadarshini, Priyanka; Suthar, Dinesh; Shah, Maanan; Jamili, Jeevankumar; Sairam, Kalapatapu V. V. M.; Giri, Suresh; Patel, Lala; Patel, Harilal; Sudani, Hareshkumar; Patel, Hiren; Jain, Mukul; Patel, Pankaj; Bahekar, RajeshBioorganic & Medicinal Chemistry Letters (2011), 21 (2), 628-632CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A novel series of oxime contg. benzyl-1,3-dioxane-r-2-carboxylic acid derivs. (6a-k) were designed as selective PPARα agonists, through bioisosteric modification in the lipophilic tail region of PPARα/γ dual agonist. Some of the test compds. (6a, 6b, 6c and 6f) showed high selectivity towards PPARα over PPARγ in vitro. Further, highly potent and selective PPARα agonist 6c (I) exhibited significant antihyperglycemic and antihyperlipidemic activity in vivo, along with its improved pharmacokinetic profile. Favorable in-silico interaction of 6c with PPARα binding pocket correlate its in vitro selectivity profile toward PPARα over PPARγ. Together, these results confirm discovery of novel series of oxime based selective PPARα agonists for the safe and effective treatment of various metabolic disorders.(b) Pingali, H.; Jain, M.; Shah, S.; Patil, P.; Makadia, P.; Zaware, P.; Sairam, K. V.; Jamili, J.; Goel, A.; Patel, M.; Patel, P. Modulation of PPAR receptor subtype selectivity of the ligands: Aliphatic chain vs aromatic ring as a spacer between pharmacophore and the lipophilic moiety. Bioorg. Med. Chem. Lett. 2008, 18, 6471– 6475, DOI: 10.1016/j.bmcl.2008.10.062[Crossref], [PubMed], [CAS], Google Scholar110bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsVWjsL7L&md5=cafedfdc3c475cb6a2eb8f8752d896d5Modulation of PPAR receptor subtype selectivity of the ligands: Aliphatic chain vs aromatic ring as a spacer between pharmacophore and the lipophilic moietyPingali, Harikishore; Jain, Mukul; Shah, Shailesh; Patil, Pravin; Makadia, Pankaj; Zaware, Pandurang; Sairam, Kalapatapu V. V. M.; Jamili, Jeevankumar; Goel, Ashish; Patel, Megha; Patel, PankajBioorganic & Medicinal Chemistry Letters (2008), 18 (24), 6471-6475CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)Oxazole contg. glycine and oximinobutyric acid derivs. were synthesized as PPARα agonists by incorporating polymethylene spacer as a replacement of commonly used phenylene group that connects the acidic head with lipophilic tail. I was found to be a selective and potent PPARα agonist. Further 1,3-dioxane-2-carboxylic acid deriv. II was synthesized by replacing the tetramethylene spacer of NS-220, a selective PPARα agonist with phenylene group and found to exhibit PPARα/γ dual agonism. These results suggest that compds. possessing polymethylene spacer between pharmacophore and lipophilic tail exhibit predominantly PPARα agonism whereas those with an arom. phenylene spacer shows PPARα/γ dual agonism.
- 111LeMahieu, R. A.; Carson, M.; Kierstead, R. W.; Fern, L. M.; Grunberg, E. Glycoside cleavage reactions on erythromycin A. Preparation of erythronolide A. J. Med. Chem. 1974, 17, 953– 956, DOI: 10.1021/jm00255a009[ACS Full Text], [CAS], Google Scholar111https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE2MXptQ%253D%253D&md5=55aad7d5aff5095162f5a240af7e5e95Glycoside cleavage reactions on erythromycin A. Preparation of erythronolide ALeMahieu, Ronald A.; Carson, Mathew; Kierstead, Richard W.; Fern, Lucy M.; Grunberg, E.Journal of Medicinal Chemistry (1974), 17 (9), 953-6CODEN: JMCMAR; ISSN:0022-2623.Selective cleavage of erythromycin A oxime [13127-18-9] by HCl-MeOH, followed by treatment with HNO2 gave 5-O-desosaminylerythronolide A (I) [53066-32-3]. Erythromycin A oxime was converted to the N-oxide [53317-21-8], which was subjected to pyrolysis, hydrolytic cleavage, and treatment with HNO2 to give erythronolide A (II) [26754-37-0]. I and II and intermediate compds. and derivs. had little or no antibacterial activity in vitro or in vivo. The activity in relation to the presence of sugar substituents was discussed.
- 112(a) Martin, R.; Plancq, B.; Gavelle, O.; Wagner, B.; Fischer, H.; Bendels, S.; Müller, K. Remote modulation of amine basicity by a phenylsulfone and a phenylthio group. ChemMedChem 2007, 2, 285– 287, DOI: 10.1002/cmdc.200600265[Crossref], [PubMed], [CAS], Google Scholar.112ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXmtVWqtLk%253D&md5=1e5681e5549ca7fc205493c7db96262bRemote modulation of amine basicity by a phenylsulfone and a phenylthio groupMartin, Rainer E.; Plancq, Baptiste; Gavelle, Olivier; Wagner, Bjorn; Fischer, Holger; Bendels, Stefanie; Muller, KlausChemMedChem (2007), 2 (3), 285-287CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)A series of Ph sulfones and phenylthioamines was studied with respect to their pKa values in water under std. conditions.(b) Morgenthaler, M.; Schweizer, E.; Hoffmann-Röder, A.; Benini, F.; Martin, R.; Jaeschke, G.; Wagner, B.; Fischer, H.; Bendels, S.; Zimmerli, D.; Schneider, J.; Diederich, F.; Kansy, M.; Müller, K. Predicting and tuning physicochemical properties in lead optimization: amine basicities. ChemMedChem 2007, 2, 1100– 1115, DOI: 10.1002/cmdc.200700059[Crossref], [PubMed], [CAS], Google Scholar112bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXpsFemsbY%253D&md5=478b70744312c01d3a43cf435d9598dePredicting and tuning physicochemical properties in lead optimization: amine basicitiesMorgenthaler, Martin; Schweizer, Eliane; Hoffmann-Roder, Anja; Benini, Fausta; Martin, Rainer E.; Jaeschke, Georg; Wagner, Bjorn; Fischer, Holger; Bendels, Stefanie; Zimmerli, Daniel; Schneider, Josef; Diederich, Francois; Kansy, Manfred; Muller, KlausChemMedChem (2007), 2 (8), 1100-1115CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. This review describes simple and useful concepts for predicting and tuning the pKa values of basic amine centers, a crucial step in the optimization of phys. and ADME properties of many lead structures in drug-discovery research. The article starts with a case study of tricyclic thrombin inhibitors featuring a tertiary amine center with pKa values that can be tuned over a wide range, from the usual value of around 10 to below 2 by (remote) neighboring functionalities commonly encountered in medicinal chem. Next, the changes in pKa of acyclic and cyclic amines upon substitution by fluorine, oxygen, nitrogen, and sulfur functionalities, as well as carbonyl and carboxyl derivs. are systematically analyzed, leading to the derivation of simple rules for pKa prediction. Electronic and stereoelectronic effects in cyclic amines are discussed, and the emerging computational methods for pKa predictions are briefly surveyed. The rules for tuning amine basicities should not only be of interest in drug-discovery research, but also to the development of new crop-protection agents, new amine ligands for organometallic complexes, and in particular, to the growing field of amine-based organocatalysis.
- 113Lenci, E.; Calugi, L.; Trabocchi, A. Occurrence of morpholine in central nervous system drug discovery. ACS Chem. Neurosci. 2021, 12, 378– 390, DOI: 10.1021/acschemneuro.0c00729[ACS Full Text], [CAS], Google Scholar113https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhtlWksrk%253D&md5=b06e6e857730c2648abc38bcbfe42a44Occurrence of Morpholine in Central Nervous System Drug DiscoveryLenci, Elena; Calugi, Lorenzo; Trabocchi, AndreaACS Chemical Neuroscience (2021), 12 (3), 378-390CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)Developing drugs for the central nervous system (CNS) requires fine chem. modifications, as a strict balance between size and lipophilicity is necessary to improve the permeability through the blood-brain barrier (BBB). In this context, morpholine and its analogs represent valuable heterocycles, due to their conformational and physicochem. properties. In fact, the presence of a weak basic nitrogen atom and of an oxygen atom at the opposite position provides a peculiar pKa value and a flexible conformation to the ring, thus allowing it to take part in several lipophilic-hydrophilic interactions, and to improve blood soly. and brain permeability of the overall structure. In CNS-active compds., morpholines are used (1) to enhance the potency through mol. interactions, (2) to act as a scaffold directing the appendages in the correct position, and (3) to modulate pharmacokinetic/pharmacodynamic (PK/PD) properties. In this perspective, selected morpholine-contg. CNS drug candidates are discussed to reveal the active pharmacophores accountable for the (1) modulation of receptors involved in mood disorders and pain, (2) bioactivity toward enzymes and receptors responsible for neurodegenerative diseases, and (3) inhibition of enzymes involved in the pathol. of CNS tumors. The medicinal chem./pharmacol. activity of morpholine derivs. is discussed, in the effort to highlight the importance of morpholine ring interactions in the active site of different targets, particularly reporting binding features retrieved from PDB data, when available.
- 114(a) Hale, J. L.; Mills, S. G.; MacCoss, M.; Shah, S. K.; Qi, H.; Mathre, D. J.; Cascieri, M. A.; Sadowski, S.; Strader, C. D.; MacIntyre, D. E.; Metzger, J. M. 2(S)-((3,5-Bis(trifluoromethyl)benzyl)-oxy)-3(S)-phenyl-4-((3-oxo-1,2,4-triazol-5-yl)methyl)morpholine (1): a potent, orally active, morpholine-based human neurokinin-1 receptor antagonist. J. Med. Chem. 1996, 39, 1760– 1762, DOI: 10.1021/jm950654w[ACS Full Text.], [CAS], Google Scholar114ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XitVaqsbg%253D&md5=8715401a42036191a1821411e8a646732(S)-((3,5-Bis(trifluoromethyl)benzyl)oxy)-3(S)-phenyl-4-((3-oxo-1,2,4-triazol-5-yl)methyl)morpholine): A Potent, Orally Active, Morpholine-Based Human Neurokinin-1 Receptor AntagonistHale, Jeffrey J.; Mills, Sander G.; MacCoss, Malcolm; Shah, Shrenik K.; Qi, Hongbo; Mathre, David J.; Cascieri, Margaret A.; Sadowski, Sharon; Strader, Catherine D.; et al.Journal of Medicinal Chemistry (1996), 39 (9), 1760-2CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The title compd., L-742694, (I) was prepd. from by the reaction of the corresponding morpholine deriv. with N-(methoxycarbonyl)-2-chloroacetamidrazone followed by thermal ring closure. Analogs of I were also prepd. I and the other morpholines represented a novel class of human neurokinin-1 receptor antagonists. Further, I is a potent, orally active member of this class that might be an important tool in the study of neurokinin pharmacol.(b) Ladduwahetty, T.; Baker, R.; Cascieri, M. A.; Chambers, M. S.; Haworth, K.; Keown, L. E.; MacIntyre, D. E.; Metzger, J. M.; Owen, S.; Rycroft, W.; Sadowski, S.; Seward, E. M.; Shepheard, S. L.; Swain, C. J.; Tattersall, F. D.; Watt, A. P.; Williamson, D. W.; Hargreaves, R. J. N-Heteroaryl-2-phenyl-3-(benzyloxy)piperidines: a novel class of potent orally active human NK1 antagonists. J. Med. Chem. 1996, 39, 2907– 2914, DOI: 10.1021/jm9506534[ACS Full Text.], [CAS], Google Scholar114bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XjvVejsbs%253D&md5=afa2309c25cebd3a418f9aeb1ce73ce9N-Heteroaryl-2-phenyl-3-(benzyloxy)piperidines: A Novel Class of Potent Orally Active Human NK1 AntagonistsLadduwahetty, T.; Baker, R.; Cascieri, M. A.; Chambers, M. S.; Haworth, K.; Keown, L. E.; MacIntyre, D. E.; Metzger, J. M.; Owen, S.; et al.Journal of Medicinal Chemistry (1996), 39 (15), 2907-2914CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The prepn. of a series of N-(heteroarylmethyl)-2-phenyl-3-[[3,5-bis(trifluoromethyl)phenyl]methoxy]piperidine I (R = 2-furanylmethyl, 4-oxazolylmethyl, 5-tetrazolylmethyl, etc.) as human NK1 antagonists was described. Two of the compds., 3-[{(2S,3S)-3-(((3,5-bis(trifluoromethyl)phenyl)methyl)oxy)-2-phenylpiperidino}methyl]-1,2,4-triazole and 5-[{(2S,3S)-3-(((3,5-bis(trifluoromethyl)phenyl)methyl)oxy)-2-phenylpiperidino}methyl]-1,2,4-triazol-3-one (II), in particular, are orally bioavailable and exhibited significant improvements in potency, both in vitro and in vivo, over the lead (carboxamidomethyl)piperidine ether L 736281. Rat liver microsome studies on a selected no. of compds. from this series show the triazolone heterocycle to be considerably more stable than the others. Furthermore, II was profiled in a no. of assays that may be predictive of the clin. utility of substance P antagonists.(c) Chen, S.; Lu, M.; Liu, D.; Yang, L.; Yi, C.; Ma, L.; Zhang, H.; Liu, Q.; Frimurer, T. M.; Wang, M.-W.; Schwartz, T. W.; Stevens, R. C.; Wu, B.; Wüthrich, K.; Zhao, Q. Human substance P receptor binding mode of the antagonist drug aprepitant by NMR and crystallography. Nat. Commun. 2019, 10, 638, DOI: 10.1038/s41467-019-08568-5[Crossref], [PubMed], [CAS], Google Scholar.114chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXns1Crurg%253D&md5=e00d2059f8f51f3ce8b20d43ea874217Human substance P receptor binding mode of the antagonist drug aprepitant by NMR and crystallographyChen, Shuanghong; Lu, Mengjie; Liu, Dongsheng; Yang, Lingyun; Yi, Cuiying; Ma, Limin; Zhang, Hui; Liu, Qing; Frimurer, Thomas M.; Wang, Ming-Wei; Schwartz, Thue W.; Stevens, Raymond C.; Wu, Beili; Wuthrich, Kurt; Zhao, QiangNature Communications (2019), 10 (1), 638CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)Neurokinin 1 receptor (NK1R) has key regulating functions in the central and peripheral nervous systems, and NK1R antagonists such as aprepitant have been approved for treating chemotherapy-induced nausea and vomiting. However, the lack of data on NK1R structure and biochem. has limited further drug development targeting this receptor. Here, we combine NMR spectroscopy and X-ray crystallog. to provide dynamic and static characterization of the binding mode of aprepitant in complexes with human NK1R variants. The 19F-NMR showed a slow off-rate in the binding site, where aprepitant occupies multiple substates that exchange with frequencies in the millisecond range. The environment of the bound ligand is affected by the amino acid in position 2.50, which plays a key role in ligand binding and receptor signaling in class A GPCRs. Crystal structures now reveal how receptor signaling relates to the conformation of the conserved NP7.50xxY motif in transmembrane helix VII.(d) Gangula, S.; Elati, C. R.; Mudunuru, S. V.; Nardela, A.; Dongamanti, A.; Bhattacharya, A.; Bandichhor, R. Synthesis of all enantiomerically pure diastereomers of aprepitant. Synth. Commun. 2010, 40, 2254– 2268, DOI: 10.1080/00397910903221084[Crossref], [CAS], Google Scholar114dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXosFCrs7Y%253D&md5=6871efa0178f38e8da50754bcd219269Synthesis of All Enantiomerically Pure Diastereomers of AprepitantGangula, Srinivas; Elati, Chandrashekhar R.; Mudunuru, Satish Varma; Nardela, Anitha; Dongamanti, Ashok; Bhattacharya, Apurba; Bandichhor, RakeshwarSynthetic Communications (2010), 40 (15), 2254-2268CODEN: SYNCAV; ISSN:0039-7911. (Taylor & Francis, Inc.)Syntheses of all eight enantiomerically pure diastereomers of aprepitant, I, and assignment of abs. configuration at newly generated stereocenters by NMR and x-ray crystallog. anal. (no data) were achieved.
- 115Hale, J. J.; Mills, S. G.; MacCoss, M.; Dorn, C. P.; Finke, P. E.; Budhu, R. J.; Reamer, R. A.; Huskey, S. W.; Luffer-Atlas, D.; Dean, B. J.; McGowan, E. M.; Feeney, W. P.; Chiu, S. L.; Cascieri, M. A.; Chicchi, G. G.; Kurtz, M. M.; Sadowski, S.; Ber, E.; Tattersall, F. D.; Rupniak, N. M.; Williams, A. R.; Rycroft, W.; Hargreaves, R.; Metzger, J. M.; MacIntyre, D. E. Phosphorylated morpholine acetal human neurokinin-1 receptor antagonists as water-soluble prodrugs. J. Med. Chem. 2000, 43, 1234– 1241, DOI: 10.1021/jm990617v[ACS Full Text], [CAS], Google Scholar115https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXht1yjtrc%253D&md5=8cabf4d88128125abb0f75fbe572eae3Phosphorylated Morpholine Acetal Human Neurokinin-1 Receptor Antagonists as Water-Soluble ProdrugsHale, Jeffrey J.; Mills, Sander G.; MacCoss, Malcolm; Dorn, Conrad P.; Finke, Paul E.; Budhu, Richard J.; Reamer, Robert A.; Huskey, Su-Er W.; Luffer-Atlas, Debra; Dean, Brian J.; McGowan, Erin M.; Feeney, William P.; Chiu, Shuet-Hing Lee; Cascieri, Margaret A.; Chicchi, Gary G.; Kurtz, Marc M.; Sadowski, Sharon; Ber, Elzbieta; Tattersall, F. David; Rupniak, Nadia M. J.; Williams, Angela R.; Rycroft, Wayne; Hargreaves, Richard; Metzger, Joseph M.; MacIntyre, D. EuanJournal of Medicinal Chemistry (2000), 43 (6), 1234-1241CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The regioselective dibenzylphosphorylation of I (R = H) followed by catalytic redn. in the presence of N-methyl-D-glucamine afforded 2-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(1-phosphoryl-3-oxo-4H,-1,2,4-triazol-5-yl)methylmorpholine, bis(N-methyl-D-glucamine) salt, II (I, R = PO3H2, bis(N-methyl-D-glucamine) salt ). Incubation in rat, dog, and human plasma and in human hepatic subcellular fractions in vitro indicated that conversion to I would be expected to occur in vivo most readily in humans during hepatic circulation. Conversion of I to II occurred rapidly in vivo in the rat and dog with the levels of II being undetectable within 5 min after 1 and 8 mg/kg doses i.v. in the rat and within 15 min after 0.5, 2, and 32 mg/kg doses i.v. in the dog. II has a 10-fold lower affinity for the human NK-1 receptor as compared to I, but it is functionally equiv. to I in preclin. models of NK-1-mediated inflammation in the guinea pig and cisplatin-induced emesis in the ferret, indicating that II acts as a prodrug of I. Based in part on these data, II was identified as a novel, water-sol. prodrug of the clin. candidate I suitable for i.v. administration in humans.
- 116(a) Fuller, N. O.; Hubbs, J. J.; Austin, W. F.; Creaser, S. P.; McKee, T. D.; Loureiro, R. M.; Tate, B.; Xia, W.; Ives, J. L.; Findeis, M. A.; Bronk, B. S. Initial optimization of a new series of γ-secretase modulators derived from a triterpene glycoside. ACS Med. Chem. Lett. 2012, 3, 908– 913, DOI: 10.1021/ml300256p[ACS Full Text.], [CAS], Google Scholar116ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xht1yhsLjO&md5=998a73e5df368087af6c75038cd74eaaInitial Optimization of a New Series of γ-Secretase Modulators Derived from a Triterpene GlycosideFuller, Nathan O.; Hubbs, Jed L.; Austin, Wesley F.; Creaser, Steffen P.; McKee, Timothy D.; Loureiro, Robyn M. B.; Tate, Barbara; Xia, Weiming; Ives, Jeffrey L.; Findeis, Mark A.; Bronk, Brian S.ACS Medicinal Chemistry Letters (2012), 3 (11), 908-913CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)The discovery of a new series of γ-secretase modulators is disclosed. Starting from a triterpene glycoside γ-secretase modulator that gave a very low brain-to-plasma ratio, initial SAR and optimization involved replacement of a pendant sugar with a series of morpholines. This modification led to two compds. with significantly improved central nervous system (CNS) exposure.(b) Hubbs, J. L.; Fuller, N. O.; Austin, W. F.; Shen, R.; Creaser, S. P.; McKee, T. D.; Loureiro, R. M.; Tate, B.; Xia, W.; Ives, J.; Bronk, B. S. Optimization of a natural product-based class of γ-secretase modulators. J. Med. Chem. 2012, 55, 9270– 9282, DOI: 10.1021/jm300976b[ACS Full Text.], [CAS], Google Scholar116bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsVGqtLfO&md5=3a826577aa836f3235a4b61468fa0c0eOptimization of a Natural Product-Based Class of γ-Secretase ModulatorsHubbs, Jed L.; Fuller, Nathan O.; Austin, Wesley F.; Shen, Ruichao; Creaser, Steffen P.; McKee, Timothy D.; Loureiro, Robyn M. B.; Tate, Barbara; Xia, Weiming; Ives, Jeffrey; Bronk, Brian S.Journal of Medicinal Chemistry (2012), 55 (21), 9270-9282CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A series of triterpene-based γ-secretase modulators is optimized. An acetate present at the C24 position of the natural product was replaced with either carbamates or ethers to provide compds. with better metabolic stability. With one of those pharmacophores in place at C24, morpholines or carbamates were installed at the C3 position to refine the physicochem. properties of the analogs. This strategy gave compds. with low clearance and good distribution into the central nervous system (CNS) of CD-1 mice. Two of these compds., I and II, were tested for a pharmacodynamic effect and exhibited statistically significant lowering of brain Aβ42 levels.(c) Loureiro, R. M.; Dumin, J. A.; McKee, T. D.; Austin, W. F.; Fuller, N. O.; Hubbs, J. L.; Shen, R.; Jonker, J.; Ives, J.; Bronk, B. S.; Tate, B. Efficacy of SPI-1865, a novel gamma-secretase modulator, in multiple rodent models. Alzheimer's Res. Ther. 2013, 5, 19, DOI: 10.1186/alzrt173[Crossref], [CAS], Google Scholar.116chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXos1Oltbc%253D&md5=f452b63f5a006a1bd8f379c64e14f6a4Efficacy of SPI-1865, a novel gamma-secretase modulator, in multiple rodent modelsLoureiro, Robyn M.; Dumin, Jo Ann; McKee, Timothy D.; Austin, Wesley F.; Fuller, Nathan O.; Hubbs, Jed L.; Shen, Ruichao; Jonker, Jeff; Ives, Jeff; Bronk, Brian S.; Tate, BarbaraAlzheimer's Research & Therapy (2013), 5 (2), 19CODEN: ARTLCD; ISSN:1758-9193. (BioMed Central Ltd.)Introduction: Modulation of the gamma-secretase enzyme, which reduces the prodn. of the amyloidogenic Aβ42 peptide while sparing the prodn. of other Aβ species, is a promising therapeutic approach for the treatment of Alzheimer's disease. Satori has identified a unique class of small mol. gamma-secretase modulators (GSMs) capable of decreasing Aβ42 levels in cellular and rodent model systems. The compd. class exhibits potency in the nM range in vitro and is selective for lowering Aβ42 and Aβ38 while sparing Aβ40 and total Aβ levels. In vivo , a compd. from the series, SPI-1865, demonstrates similar pharmacol. in wild-type CD1 mice, Tg2576 mice and Sprague Dawley rats. Methods: Animals were orally administered either a single dose of SPI-1865 or dosed for multiple days. Aβ levels were measured using a sensitive plate-based ELISA system (MSD) and brain and plasma exposure of drug were assessed by LC/MS/MS. Results: In wild-type mice using either dosing regimen, brain Aβ42 and Aβ38 levels were decreased upon treatment with SPI-1865 and little to no statistically meaningful effect on Aβ40 was obsd., reflecting the changes obsd. in vitro. In rats, brain Aβ levels were examd. and similar to the mouse studies, brain Aβ42 and Aβ38 were lowered. Comparable changes were also obsd. in the Tg2576 mice, where Aβ levels were measured in brain as well as plasma and CSF. Conclusions: Taken together, these data indicate that SPI-1865 is orally bioavailable, brain penetrant, and effective at lowering Aβ42 in a dose responsive manner. With this unique profile, the class of compds. represented by SPI-1865 may be a promising new therapy for Alzheimer's disease.(d) Fuller, N. O.; Hubbs, J. L.; Austin, W. F.; Shen, R.; Ives, J.; Osswald, G.; Bronk, B. S. Optimization of a Kilogram-Scale Synthesis of a Potent Cycloartenol Triterpenoid-Derived γ-Secretase Modulator. Org. Process Res. Dev. 2014, 18, 683– 692, DOI: 10.1021/op500072b[ACS Full Text], [CAS], Google Scholar116dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXnt1CnsLs%253D&md5=a65f49d808414d1a4d77c1bd71730b00Optimization of a Kilogram-Scale Synthesis of a Potent Cycloartenol Triterpenoid-Derived γ-Secretase ModulatorFuller, Nathan O.; Hubbs, Jed L.; Austin, Wesley F.; Shen, Ruichao; Ives, Jeffrey; Osswald, Gerd; Bronk, Brian S.Organic Process Research & Development (2014), 18 (6), 683-692CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)This work describes the demonstration of a kilogram-scale synthesis of a γ-secretase modulator from a plant-sterol-derived starting material. Key to developing a synthetic route capable of delivering a kilogram of the target compd. I was the development of a four-reaction telescope process and a selective O-alkylation of a triol intermediate. These improvements enabled the successful delivery of kilogram-scale batches of API for preclin. development studies.
- 117(a) Kaneko, S.; Arai, M.; Uchida, T.; Harasaki, T.; Fukuoka, T.; Konosu, T. Synthesis and evaluation of N-substituted 1,4-oxazepanyl sordaricins as selective fungal EF-2 inhibitors. Bioorg. Med. Chem. Lett. 2002, 12, 1705– 1708, DOI: 10.1016/S0960-894X(02)00290-1[Crossref], [PubMed], [CAS], Google Scholar.117ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38Xktlyls70%253D&md5=390431805ed396121ad9de3fa2a4440cSynthesis and evaluation of N-substituted 1,4-oxazepanyl sordaricins as selective fungal EF-2 inhibitorsKaneko, Satoru; Arai, Masami; Uchida, Takuya; Harasaki, Tamako; Fukuoka, Takashi; Konosu, ToshiyukiBioorganic & Medicinal Chemistry Letters (2002), 12 (13), 1705-1708CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)Sordaricin analogs, e.g. I, possessing 6-methoxy-7-methyl-1,4-oxazepane moiety instead of the sugar part were synthesized and evaluated. It was found that N-substituents on the oxazepane ring had influence on biol. activity. In particular, N-(2-methylpropenyl) deriv. I exhibited potent in vitro antifungal activity. Furthermore, I maintained significant activity (MIC 0.25 μg/mL) against Candida albicans SANK51486 even in the presence of 20% horse serum.(b) Arai, M.; Harasaki, T.; Fukuoka, T.; Kaneko, S.; Konosu, T. Synthesis and evaluation of novel pyrrolidinyl sordaricin derivatives as antifungal agents. Bioorg. Med. Chem. Lett. 2002, 12, 2733– 2736, DOI: 10.1016/S0960-894X(02)00534-6[Crossref], [PubMed], [CAS], Google Scholar.117bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XmslGisb0%253D&md5=5f040aee26f60198e5164d1d36d87e6cSynthesis and evaluation of novel pyrrolidinyl sordaricin derivatives as antifungal agentsArai, Masami; Harasaki, Tamako; Fukuoka, Takashi; Kaneko, Satoru; Konosu, ToshiyukiBioorganic & Medicinal Chemistry Letters (2002), 12 (19), 2733-2736CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)N-Benzyl pyrrolidinyl sordaricin derivs. were synthesized in a stereocontrolled manner. These compds. maintained moderate antifungal activity against several pathogenic fungal strains. Their MIC values against Candida albicans were in the range of 0.25-2 μg/mL.(c) Serrano-Wu, M. H.; St. Laurent, D. R.; Chen, Y.; Huang, S.; Lam, K.-R.; Matson, J. A.; Mazzucco, C. E.; Stickle, T. M.; Tully, T. P.; Wong, H. S.; Vyas, D. M.; Balasubramanian, B. N. Sordarin oxazepine derivatives as potent antifungal agents. Bioorg. Med. Chem. Lett. 2002, 12, 2757– 2760, DOI: 10.1016/S0960-894X(02)00529-2[Crossref], [PubMed], [CAS], Google Scholar.117chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XmslGisLc%253D&md5=160441705dcaf29deaffb71e4787d47dSordarin Oxazepine Derivatives as Potent Antifungal AgentsSerrano-Wu, Michael H.; St. Laurent, Denis R.; Chen, Yijun; Huang, Stella; Lam, Kin-Ray; Matson, James A.; Mazzucco, Charles E.; Stickle, Terry M.; Tully, Thomas P.; Wong, Henry S.; Vyas, Dolatrai M.; Balasubramanian, Balu N.Bioorganic & Medicinal Chemistry Letters (2002), 12 (19), 2757-2760CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)The synthesis and biol. activity of sordarin oxazepine derivs., i.e. I, are described. The key step features a regioselective oxidn. of an unprotected triol followed by double reductive amination to afford the ring-closed products. The spectrum of antifungal activity for these novel derivs. includes coverage of Candida albicans, Candida glabrata, and Cryptococcus neoformans.(d) Serrano-Wu, M. H.; Laurent, D. R.S..; Carroll, T. M.; Dodier, M.; Gao, Q.; Gill, P.; Quesnelle, C.; Marinier, A.; Mazzucco, C. E.; Regueiro-Ren, A.; Stickle, T. M.; Wu, D.; Yang, H.; Yang, Z.; Zheng, M.; Zoeckler, M. E.; Vyas, D. M.; Balasubramanian, B. N. Identification of a broad-spectrum azasordarin with improved pharmacokinetic properties. Bioorg. Med. Chem. Lett. 2003, 13, 1419– 1423, DOI: 10.1016/S0960-894X(03)00161-6[Crossref], [PubMed], [CAS], Google Scholar.117dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXis1aqt74%253D&md5=db58c24820243710440e21dd1d43bbf9Identification of a broad-Spectrum azasordarin with improved pharmacokinetic propertiesSerrano-Wu, Michael H.; St. Laurent, Denis R.; Carroll, Tina M.; Dodier, Marco; Gao, Qi; Gill, Patrice; Quesnelle, Claude; Marinier, Anne; Mazzucco, Charles E.; Regueiro-Ren, Alicia; Stickle, Terry M.; Wu, Dedong; Yang, Hyekyung; Yang, Zheng; Zheng, Ming; Zoeckler, Mary E.; Vyas, Dolatrai M.; Balasubramanian, Balu N.Bioorganic & Medicinal Chemistry Letters (2003), 13 (8), 1419-1423CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science B.V.)The synthesis and antifungal activity of 5'- and 5'-6'-substituted azasordarin derivs. I [R4 = CH2CCl:CH2, R5 = H, Me, R6 = Me; R4 = CH2CCl:CH2, R5R6 = cyclopentyl; R4 = CH2CCl:CH2, R5 = Me, CHMe2, CH2OH, CF3, spirocyclopentyl, R6 = H; R4 = CH2CBr:CH2, CH2CH:CH2 CH2CMe:CH2, CH2C(CN):CH2, CH2CH:CHCl-cis, CH2CH:CHBr-cis, CH2CH:CCl2, CH2CH:CF2, CH2CH:CMe2, cyclohex-2-enyl, cyclopropylmethyl, iso-Bu, CH2C6H4OMe-4, CH2C6H2Cl-2, 5-chloro-2-thienyl, COCH:CH2, cyclopropylsulfonyl, R5 = Me, R6 = H] are described. Modification of the 5'-position led to the discovery of the spirocyclopentyl analog I (R4 = CH2CCl:CH2, R5 = spirocyclopentyl, R6 = H), which is the first azasordarin to register single-digit MIC values vs. Aspergillus spp. Further investigation identified the 5'-i-Pr deriv. I (R4 = CH2CCl:CH2, R5 = CHMe2, R6 = H), which displays superior pharmacokinetic properties compared to other azasordarins.(e) Kamai, Y.; Kakuta, M.; Shibayama, T.; Fukuoka, T.; Kuwahara, S. Antifungal activities of R-135853, a sordarin derivative, in experimental candidiasis in mice. Antimicrob. Agents Chemother. 2005, 49, 52– 56, DOI: 10.1128/AAC.49.1.52-56.2005[Crossref], [PubMed], [CAS], Google Scholar117ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXjsl2qsQ%253D%253D&md5=89df046e4475e8a761146613dbec231aAntifungal activities of R-135853, a sordarin derivative, in experimental candidiasis in miceKamai, Yasuki; Kakuta, Masayo; Shibayama, Takahiro; Fukuoka, Takashi; Kuwahara, ShogoAntimicrobial Agents and Chemotherapy (2005), 49 (1), 52-56CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)The activities of R-135853, a novel sordarin deriv. that possesses a 1,4-oxazepane ring moiety, were evaluated in vitro and in vivo. R-135853 exhibited potent in vitro activities against Candida albicans (fluconazole-susceptible strains), Candida glabrata, Candida tropicalis, and Cryptococcus neoformans, with MICs at which 90% of isolates were inhibited of 0.03, 1, 0.5, and 0.5 μg/mL, resp. R-135853 also exhibited potent activities against fluconazole-susceptible dose-dependent and fluconazole-resistant strains of C. albicans, with MICs ranging from 0.03 to 0.06 μg/mL. However, R-135853 exhibited weak or no activity against Candida parapsilosis, Candida krusei, and Aspergillus spp. R-135853 exhibited dose-dependent efficacy against exptl. murine hematogenous candidiasis induced by C. albicans when it was administered by both the s.c. and the oral routes and reduced viable cell counts in the kidneys significantly when it was administered at 50 mg/kg of body wt./dose (administration three times a day). In this model, R-135853 also exhibited dose-dependent efficacy by single oral administration. S.c. administration of R-135853 exhibited dose-dependent efficacy against exptl. murine esophageal candidiasis induced by fluconazole-resistant C. albicans, against which fluconazole at 50 mg/kg/dose was ineffective, and reduced viable cell counts in the esophagus significantly when it was administered at 10 and 50 mg/kg/dose. R-135853 eradicated C. albicans from the esophagi of one and four of five mice when it was administered at 10 and 50 mg/kg/dose, resp. These results suggest that R-135853 is promising for the treatment of disseminated or mucosal candidiasis, including fluconazole-refractory infections.
- 118Bueno, A. B.; Agejas, J.; Broughton, H.; Dally, R.; Durham, T. B.; Espinosa, J. F.; Gonzalez, R.; Hahn, P. J.; Marcos, A.; Rodríguez, R.; Sanz, G.; Soriano, J. F.; Timm, D.; Vidal, P.; Yang, H.; McCarthy, J. R. Optimization of hydroxyethylamine transition state isosteres as aspartic protease inhibitors by exploiting conformational preferences. J. Med. Chem. 2017, 60, 9807– 9820, DOI: 10.1021/acs.jmedchem.7b01304[ACS Full Text], [CAS], Google Scholar118https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhslCitb%252FO&md5=7baa111e22231813b64aed6a21181eedOptimization of Hydroxyethylamine Transition State Isosteres as Aspartic Protease Inhibitors by Exploiting Conformational PreferencesBueno, Ana B.; Agejas, Javier; Broughton, Howard; Dally, Robert; Durham, Timothy B.; Espinosa, Juan Felix; Gonzalez, Rosario; Hahn, Patric J.; Marcos, Alicia; Rodriguez, Ramon; Sanz, Gema; Soriano, Jose F.; Timm, David; Vidal, Paloma; Yang, Hsiu-Chiung; McCarthy, James R.Journal of Medicinal Chemistry (2017), 60 (23), 9807-9820CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)NMR Conformational anal. of a hydroxyethylamine peptide isostere developed as an aspartic protease inhibitor shows that it is a flexible architecture. Cyclization to form pyrrolidines, piperidines or morpholines results in a preorganization of the whole system in soln. The resulting conformation is similar to the conformation of the inhibitor in the active site of BACE-1. This entropic gain results in increased affinity for the enzyme when compared with the acyclic system. For morpholines 27 and 29, the combination of steric and electronic factors was exploited to orient substituents toward S1, S1' and S2' pockets both in the soln. and in the bound states. These highly preorganized mols. proved to be the most potent compds. of the series. Addnl., the morpholines, unlike the pyrrolidine and piperidine analogs, were found to be brain penetrant BACE-1 inhibitors.
- 119(a) Eliel, E. I.; Alcudia, F. Acetylcholine analogues. Conformational equilibriums dominated by electrostatic interactions. J. Am. Chem. Soc. 1974, 96, 1939– 1941, DOI: 10.1021/ja00813a051[ACS Full Text.], [CAS], Google Scholar119ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE2cXktVehtro%253D&md5=840e7d2d863d9e59bb7c95aa88fbf1b5Acetylcholine analogs. Conformational equilibriums dominated by electrostatic interactionsEliel, Ernest I.; Alcudia, FelipeJournal of the American Chemical Society (1974), 96 (6), 1939-41CODEN: JACSAT; ISSN:0002-7863.The acid catalyzed equilibration of 2-isopropyl-5-ammonio-, 2-isopropyl-5-dimethylammonio-, 2-isopropyl-5-trimethylammonio- and 2-isopropyl-5-dimethylsulfonio-1,3-dioxane salts favor the axial (cis) isomer by over 2 kcal/mole in all cases. The results are explained on the basis of electrostatic attraction of the positively charged axial substituent and the ring O atoms. The bearing of these findings on the preferred gauche conformation of acetylcholine and the reasons therefore are discussed. H bonding is probably not important in favoring the gauche or axial conformations.(b) Kaloustian, M. K.; Dennis, N.; Mager, S.; Evans, S. A.; Alcudia, F.; Eliel, E. I. Conformational analysis. XXXI. Conformational equilibria of 1,3-dioxanes with polar substituents at C-5. J. Am. Chem. Soc. 1976, 98, 956– 965, DOI: 10.1021/ja00420a015[ACS Full Text], [CAS], Google Scholar119bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE28XhtlCrurc%253D&md5=41c42337be5653ce6a4a0050823da5c2Conformational analysis. XXXI. Conformational equilibria of 1,3-dioxanes with polar substituents at C-5Kaloustian, Moses K.; Dennis, Nicholas; Mager, Sorin; Evans, Slayton A.; Alcudia, Felipe; Eliel, Ernest L.Journal of the American Chemical Society (1976), 98 (4), 956-65CODEN: JACSAT; ISSN:0002-7863.Free energies of isomerization (ΔG°) of isopropyldioxanes (I .dblharw. II; R = CH2OMe, COMe, CO2-, SO2Me, etc.) are reported and compared with previously published data (Eliel, E. L. et al, 1967, 1972, 1973). In a no. of these cases, I are favored at equilibrium even though either steric or dipolar considerations would lead to the opposite prediction. Explanations based on internal solvation, orbital interaction, and charge attractions are considered.
- 120Pasternak, A.; Pan, Y.; Marino, D.; Sanderson, P. E.; Mosley, R.; Rohrer, S. P.; Birzin, E. T.; Huskey, S. W.; Jacks, T.; Schleim, K. D.; Cheng, K.; Schaeffer, J. M.; Patchett, A. A.; Yang, L. Potent, orally bioavailable somatostatin agonists: good absorption achieved by urea backbone cyclization. Bioorg. Bioorg. Med. Chem. Lett. 1999, 9, 491– 496, DOI: 10.1016/S0960-894X(99)00016-5[Crossref], [PubMed], [CAS], Google Scholar120https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXhslSlsr0%253D&md5=31b323b2426b1467b3a92868a1e9b56aPotent, orally bioavailable somatostatin agonists: good absorption achieved by urea backbone cyclizationPasternak, Alexander; Pan, Yanping; Marino, Dominick; Sanderson, Philip E.; Mosley, Ralph; Rohrer, Susan P.; Birzin, Elizabeth T.; Huskey, Su-Er Wu; Jacks, Tom; Schleim, Klaus D.; Cheng, Kang; Schaeffer, James M.; Patchett, Arthur A.; Yang, LihuBioorganic & Medicinal Chemistry Letters (1999), 9 (3), 491-496CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)Backbone cyclization of urea-based somatostatin agonists resulted in novel, orally bioavailable agonists. Binding assays confirmed that the resulting conformationally constrained cyclic ureas retained the potency of their acyclic counterparts. SAR studies subsequently led to highly potent analogs, selective for receptor subtype 2, and having good oral bioavailability.
- 121(a) Li, L.; Okumu, A.; Dellos-Nolan, S.; Li, Z.; Karmahapatra, S.; English, A.; Yalowich, J. C.; Wozniak, D. J.; Mitton-Fry, M. J. Synthesis and anti-staphylococcal activity of novel bacterial topoisomerase inhibitors with a 5-amino-1,3-dioxane linker moiety. Bioorg. Med. Chem. Lett. 2018, 28, 2477– 2480, DOI: 10.1016/j.bmcl.2018.06.003[Crossref], [PubMed], [CAS], Google Scholar.121ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtVOls77M&md5=d510bc73c8fd04d11fb1b7e0f069198bSynthesis and anti-staphylococcal activity of novel bacterial topoisomerase inhibitors with a 5-amino-1,3-dioxane linker moietyLi, Linsen; Okumu, Antony; Dellos-Nolan, Sheri; Li, Zoe; Karmahapatra, Soumendrakrishna; English, Anthony; Yalowich, Jack C.; Wozniak, Daniel J.; Mitton-Fry, Mark J.Bioorganic & Medicinal Chemistry Letters (2018), 28 (14), 2477-2480CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Novel bacterial type II topoisomerase inhibitors (NBTIs) constitute a promising new class of antibacterial agents. The authors report a series of NBTIs with potent anti-staphylococcal activity and diminished hERG inhibition. Dioxane-linked compd. N-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-2-(2-(6-methoxyquinolin-4-yl)ethyl)-trans-1,3-dioxan-5-amine demonstrated MICs ≤1μg/mL against both methicillin-susceptible (MSSA) and -resistant Staphylococcus aureus (MRSA), accompanied by reduced hERG inhibition as compared to cyclohexane- or piperidine-linked analogs.(b) Lu, Y.; Papa, J. L.; Nolan, S.; English, A.; Seffernick, J. T.; Shkolnikov, N.; Powell, J.; Lindert, S.; Wozniak, D. J.; Yalowich, J.; Mitton-Fry, M. J. Dioxane-linked amide derivatives as novel bacterial topoisomerase inhibitors against Gram-positive Staphylococcus aureus. ACS Med. Chem. Lett. 2020, 11, 2446– 2454, DOI: 10.1021/acsmedchemlett.0c00428[ACS Full Text], [CAS], Google Scholar121bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXitVynsL7L&md5=1bfec4b3fef8315a4d5b41707b204191Dioxane-Linked Amide Derivatives as Novel Bacterial Topoisomerase Inhibitors against Gram-Positive Staphylococcus aureusLu, Yanran; Papa, Jonathan L.; Nolan, Sheri; English, Anthony; Seffernick, Justin T.; Shkolnikov, Nicholas; Powell, Josh; Lindert, Steffen; Wozniak, Daniel J.; Yalowich, Jack; Mitton-Fry, Mark J.ACS Medicinal Chemistry Letters (2020), 11 (12), 2446-2454CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)In recent years, novel bacterial topoisomerase inhibitors (NBTIs) have been developed as future antibacterials for treating multidrug-resistant bacterial infections. A series of dioxane-linked NBTIs with an amide moiety has been synthesized and evaluated. Compd. 3 inhibits DNA gyrase, induces the formation of single strand breaks to bacterial DNA, and achieves potent antibacterial activity against a variety of Gram-pos. pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). Optimization of this series of analogs led to the discovery of a subseries of compds. (22-25) with more potent anti-MRSA activity, dual inhibition of DNA gyrase and topoisomerase IV, and the ability to induce double strand breaks through inhibition of S. aureus DNA gyrase.
- 122Kemp, J. A.; Keebaugh, A.; Edson, J. A.; Chow, D.; Kleinman, M. T.; Chew, Y. C.; McCracken, A. N.; Edinger, A. L.; Kwon, Y. J. Biocompatible chemotherapy for leukemia by acid-cleavable, PEGylated FTY720. Bioconjugate Chem. 2020, 31, 673– 684, DOI: 10.1021/acs.bioconjchem.9b00822[ACS Full Text], [CAS], Google Scholar122https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhs1Smt7o%253D&md5=11a9138ce2f13a57783e75a5275561c4Biocompatible Chemotherapy for Leukemia by Acid-Cleavable, PEGylated FTY720Kemp, Jessica A.; Keebaugh, Andrew; Edson, Julius A.; Chow, David; Kleinman, Michael T.; Chew, Yap Ching; McCracken, Alison N.; Edinger, Aimee L.; Kwon, Young JikBioconjugate Chemistry (2020), 31 (3), 673-684CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)Targeting the inability of cancerous cells to adapt to metabolic stress is a promising alternative to conventional cancer chemotherapy. FTY720 (Gilenya), an FDA-approved drug for the treatment of multiple sclerosis, has recently been shown to inhibit cancer progression through the down-regulation of essential nutrient transport proteins, selectively starving cancer cells to death. However, the clin. use of FTY720 for cancer therapy is prohibited because of its capability of inducing immunosuppression (lymphopenia) and bradycardia when phosphorylated upon administration. A prodrug to specifically prevent phosphorylation during circulation, hence avoiding bradycardia and lymphopenia, was synthesized by capping its hydroxyl groups with polyethylene glycol (PEG) via an acid-cleavable ketal linkage. Improved aq. soly. was also accomplished by PEGylation. The prodrug reduces to fully potent FTY720 upon cellular uptake and induces metabolic stress in cancer cells. Enhanced release of FTY720 at a mildly acidic endosomal pH and the ability to substantially down-regulate cell-surface nutrient transporter proteins in leukemia cells only by an acid-cleaved drug were confirmed. Importantly, the prodrug demonstrated nearly identical efficacy to FTY720 in an animal model of BCR-Abl-driven leukemia without inducing bradycardia or lymphopenia in vivo, highlighting its potential clin. value. The prodrug formulation of FTY720 demonstrates the utility of precisely engineering a drug to avoid undesirable effects by tackling specific mol. mechanisms as well as a financially favorable alternative to new drug development. A multitude of existing cancer therapeutics may be explored for prodrug formulation to avoid specific side effects and preserve or enhance therapeutic efficacy.
- 123Kirby, A. J.; Percy, J. M. Intramolecular proton-transfer catalysis of nucleophilic catalysis of acetal hydrolysis. The hydrolysis of 8-dimethylamino-1-methoxymethoxynaphthalene. J. Chem. Soc., Perkin Trans. 2 1989, 907– 912, DOI: 10.1039/p29890000907[Crossref], [CAS], Google Scholar123https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3cXlsVGkug%253D%253D&md5=a8ed0fab44024fda0df689264221e58cIntramolecular proton-transfer catalysis of nucleophilic catalysis of acetal hydrolysis. The hydrolysis of 8-(dimethylamino)-1-(methoxymethoxy)naphthaleneKirby, Anthony J.; Percy, Jonathan M.Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999) (1989), (7), 907-12CODEN: JCPKBH; ISSN:0300-9580.The cleavage of the conjugate acid of the title aryl Me acetal is catalyzed efficiently by the neighboring Me2NH+ group, and also by added nucleophiles. Hydrolysis and nucleophilic catalysis involve a common mechanism, with obligatory but weak bonding to water or the added nucleophile in the transition state. The key to efficient intramol. proton-transfer catalysis appears to be an intramol. hydrogen bond between the general acid and the leaving-group oxygen which is strong in the product and transition states, but weak or absent in the ground state.
- 124(a) Bi, L.; Zhao, M.; Gu, K.; Wang, C.; Ju, J.; Peng, S. Toward the development of chemoprevention agents (III): Synthesis and anti-inflammatory activities of a new class of 5-glycylamino-2-substituted-phenyl-1,3-dioxacycloalkanes. Bioorg. Med. Chem. 2008, 16, 1764– 1774, DOI: 10.1016/j.bmc.2007.11.017[Crossref], [PubMed], [CAS], Google Scholar.124ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXitVOjurc%253D&md5=ed0bcf0a957f6b39bc3c5ddf41613223Toward the development of chemoprevention agents (III): Synthesis and anti-inflammatory activities of a new class of 5-glycylamino-2-substituted-phenyl-1,3-dioxacycloalkanesBi, Lanrong; Zhao, Ming; Gu, Keli; Wang, Chao; Ju, Jingfang; Peng, ShiqiBioorganic & Medicinal Chemistry (2008), 16 (4), 1764-1774CODEN: BMECEP; ISSN:0968-0896. (Elsevier Ltd.)A new series of 5-glycylamino-2-substituted-phenyl-1,3-dioxacycloalkanes were designed and synthesized. The anti-inflammatory activities of these compds. were tested using the xylene-induced mouse ear edema model. Sixteen of these new compds. exhibited comparable or better anti-inflammatory activities than aspirin suggesting that they can be further developed as potential anti-inflammatory drug leads. In addn., treatment with these anti-inflammatory agents did not prolong tail bleeding time in mice. The structure/activity relationships were also analyzed among these compds. Considering their good efficacy and safety profiles, some 5-glycylamino-2-substituted-phenyl-1,3-dioxacycloalkanes are worthy to be explored further in assessing the possible link between anti-inflammation and cancer prevention.(b) Bi, L.; Zhang, Y.; Zhao, M.; Wang, C.; Chan, P.; Tok, J. B.-H.; Peng, S. Novel synthesis and anti-inflammatory activities of 2,5-disubstituted-dioxacycloalkanes. Bioorg. Med. Chem. 2005, 13, 5640– 5646, DOI: 10.1016/j.bmc.2005.05.032[Crossref], [PubMed], [CAS], Google Scholar124bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXos1ajs7Y%253D&md5=c013d9d82952efc7871fdc65c397d36bNovel synthesis and anti-inflammatory activities of 2,5-disubstituted-dioxacycloalkanesBi, Lanrong; Zhang, Yue; Zhao, Ming; Wang, Chao; Chan, Priscilla; Tok, Jeffrey B.-H.; Peng, ShiqiBioorganic & Medicinal Chemistry (2005), 13 (19), 5640-5646CODEN: BMECEP; ISSN:0968-0896. (Elsevier Ltd.)A novel stereospecific synthetic route to obtain a series of 2,5-disubstituted-dioxacycloalkanes is reported. Using an in vivo inhibition assay by monitoring xylene-induced ear edema in mice, the structure-activity relationship of the dioxacycloalkane compds. was studied, and compds. possessing high anti-inflammatory activity were identified.
- 125(a) Dovgan, I.; Kolodych, S.; Koniev, O.; Wagner, A. 2-(Maleimidomethyl)-1,3-dioxanes (MD): a serum-stable self-hydrolysable hydrophilic alternative to classical maleimide conjugation. Sci. Rep. 2016, 6, 30835, DOI: 10.1038/srep30835[Crossref], [PubMed], [CAS], Google Scholar.125ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtlCisbbO&md5=6be2bf9187983ec52f6650841df724e32-(Maleimidomethyl)-1,3-Dioxanes (MD): a Serum-Stable Self-hydrolysable Hydrophilic Alternative to Classical Maleimide ConjugationDovgan, Igor; Kolodych, Sergii; Koniev, Oleksandr; Wagner, AlainScientific Reports (2016), 6 (), 30835CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)The vast majority of antibody-drug conjugates (ADC) are prepd. through amine-to-thiol conjugation. To date, N-Succinimidyl-4-(maleimidomethyl) cyclohexanecarboxylate (SMCC) has been one of the most frequently applied reagents for the prepn. of ADC and other functional conjugates. However, SMCC-based conjugates suffer from limited stability in blood circulation and from a hydrophobic character of the linker, which may give rise to major pharmacokinetic implications. To address this issue, we have developed a heterobifunctional analog of a SMCC reagent, i.e., sodium 4-((maleimidomethyl-1,3-dioxane-5-carbonyl)oxy)-2,3,5,6- tetrafluorobenzenesulfonate (MDTF) for amine-to-thiol conjugation. By replacing the cyclohexyl ring in the SMCC structure with the 1,3-dioxane, we increased the hydrophilicity of the linker. A FRET probe based on MD linker was prepd. and showed superior stability compared to the MCC linker in human plasma, as well as in a variety of aq. buffers. A detailed investigation demonstrated an accelerated succinimide ring opening for MD linker, resulting in stabilized conjugates. Finally, the MDTF reagent was applied for the prepn. of serum stable antibody-dye conjugate.(b) Tobaldi, E.; Dovgan, I.; Mosser, M.; Becht, J.-M.; Wagner, A. Structural investigation of cyclo-dioxo maleimide cross-linkers for acid and serum stability. Org. Biomol. Chem. 2017, 15, 9305– 9310, DOI: 10.1039/C7OB01757J[Crossref], [PubMed], [CAS], Google Scholar125bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhslCnu7rF&md5=5969f8aea1e535eb15feb2951e22ad4aStructural investigation of cyclo-dioxo maleimide cross-linkers for acid and serum stabilityTobaldi, Elisabetta; Dovgan, Igor; Mosser, Michel; Becht, Jean-Michel; Wagner, AlainOrganic & Biomolecular Chemistry (2017), 15 (44), 9305-9310CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)The biochem. characteristics of hetero-bifunctional cross-linkers used in bioconjugates are of essential importance to the desired features of the final adduct (i.e. antibody-drug conjugates). These include stability in biol. media, chem. and biol. reactivities, cleavability under defined conditions, and soly. In our previous work, we introduced a new amino-to-thiol linker, maleimidomethyldioxane (MD), as an alternative to classical maleimide conjugation, with increased hydrophilicity and serum stability due to succinimidyl ring-opening. In this work, we investigated the generality of linkers contg. a dioxo-ring with regard to their ability to self-hydrolyze and their surprising stability at a low pH. We synthesized 3 FRET probes which allowed us to address the stability of the dioxo-ring and to study the maleimide ring-opening and the thiol-exchange processes by means of detecting and measuring the generation of fluorescence. It was found that the ring expansion (from a 5- to a 6-membered ring) improved the stability of the probes in aq. media, and the increase of the chain length between the dioxo-ring and the succinimide ring (from methylene to ethylene) decreased the rate of succinimidyl ring-opening.
- 126Maertens, J. A. History of the development of azole derivatives. Clin. Microbiol. Infect. 2004, 10, 1– 10, DOI: 10.1111/j.1470-9465.2004.00841.x[Crossref], [PubMed], [CAS], Google Scholar126https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXjtFymu7Y%253D&md5=d57e2d90d93844d58562d357652fd1d7History of the development of azole derivativesMaertens, J. A.Clinical Microbiology and Infection (2004), 10 (Suppl. 1), 1-10CODEN: CMINFM; ISSN:1198-743X. (Blackwell Publishing Ltd.)A review. Until the 1940s, relatively few agents were available for the treatment of systemic fungal infections. The development of the polyene antifungals represented a major advance in medical mycol. Although amphotericin B quickly became the mainstay of therapy for serious infections, its use was assocd. with infusion-related side-effects and dose-limiting nephrotoxicity. The continued search for new and, less toxic antifungals led to the discovery of the azoles several decades later. Ketoconazole, the first available compd. for the oral treatment of systemic fungal infections, was released in the early 1980s. For almost a decade, ketoconazole was regarded as the drug of choice in nonlife-threatening endemic mycoses. The introduction of the first-generation triazoles represented a second major advance in the treatment of fungal infections. Both fluconazole and itraconazole displayed a broader spectrum of antifungal activity than the imidazoles and had a markedly improved safety profile compared with amphotericin B and ketoconazole. Despite widespread use, however, these agents became subject to a no. of clin. important limitations related to their suboptimal spectrum of activity, the development of resistance, the induction of hazardous drug-drug interactions, their less than optimal pharmacokinetic profile (itraconazole capsules), and toxicity. To overcome these limitations, several analogs have been developed. These so-called 'second-generation' triazoles, including voriconazole, posaconazole and ravuconazole, have greater potency and possess increased activity against resistant and emerging pathogens, in particular against Aspergillus spp. If the toxicity profile of these agents is comparable to or better than that of the first-generation triazoles and drug interactions remain manageable, then these compds. represent a true expansion of our antifungal arsenal.
- 127Heeres, J.; Backx, L. J. J.; Mostmans, J. H.; Van Cutsem, J. Antimycotic imidazoles. Part 4. Synthesis and antifungal activity of ketoconazole, a new potent orally active broad-spectrum antifungal agent. J. Med. Chem. 1979, 22, 1003– 1005, DOI: 10.1021/jm00194a023[ACS Full Text], [CAS], Google Scholar127https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE1MXks1ymsrc%253D&md5=2e33090d948cc691b14e01a8d371093dAntimycotic imidazoles. Part 4. Synthesis and antifungal activity of ketoconazole, a new potent orally active broad-spectrum antifungal agentHeeres, J.; Backx, L. J. J.; Mostmans, J. H.; Van Cutsem, J.Journal of Medicinal Chemistry (1979), 22 (8), 1003-5CODEN: JMCMAR; ISSN:0022-2623.Ketoconazole (I) [65277-42-1], prepd. from 2,4-dichloroacetophenone [2234-16-4], had complete or marked growth inhibitory activity against a no. of fungi and bacteria. The antifungal effect of I in vitro depended on the test medium. In vivo, I given orally, was effective against exptl. cutaneous candidosis in guinea pigs and vaginal candidosis in rats.
- 128(a) Vanden Bossche, H.; Heeres, J.; Backx, L. J. J.; Marichal, P.; Willemsens, G. Discovery, chemistry, mode of action, and selectivity of itraconazole. In Cutaneus Antifungal Agents; Rippon, J. W., Fromtling, R. A., Eds.; Marcel Decker Inc.: New York, 1993; pp 263– 283.(b) Martin, M. V. The use of fluconazole and itraconazole in the treatment of Candida albicans infections: a review. J. Antimicrob. Chemother. 1999, 44, 429– 437, DOI: 10.1093/jac/44.4.429[Crossref], [PubMed], [CAS], Google Scholar128bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXntV2lurs%253D&md5=e3f831937fab31bb98569375c7f4f1f2The use of fluconazole and itraconazole in the treatment of Candida albicans infections: a reviewMartin, Michael V.Journal of Antimicrobial Chemotherapy (1999), 44 (4), 429-437CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)A review with 93 refs. Candida albicans is responsible for most fungal infections in humans. Fluconazole is well established as a first-line management option for the treatment and prophylaxis of localized and systemic C. albicans infections. Fluconazole exhibits predictable pharmacokinetics and is effective, well tolerated and suitable for use in most patients with C. albicans infections, including children, the elderly and those with impaired immunity. Prophylactic administration of fluconazole can help to prevent fungal infections in patients receiving cytotoxic cancer therapy. The increasing use of fluconazole for the long-term prophylaxis and treatment of recurrent oral candidosis in AIDS patients has led to the emergence of C. albicans infections that are not responsive to conventional doses. Second-line therapy with a wider spectrum anti-fungal, such as itraconazole, should be sought if treatment with fluconazole fails. A soln. formulation of itraconazole has recently been introduced to overcome the poor and variable absorption of its original capsule formulation. Efficacy and tolerability studies in HIV-pos. or immunocompromised patients with C. albicans infections have shown that, although itraconazole soln. is as effective as fluconazole, it is less well tolerated as first-line therapy. Itraconazole soln. can be effective in AIDS patients with C. albicans infections that are non-responsive to fluconazole. No efficacy or tolerability data are available on the use of itraconazole soln. in children or the elderly.
- 129Fukami, T.; Iida, A.; Konishi, K.; Nakajima, M. Human arylacetamide deacetylase hydrolyzes ketoconazole to trigger hepatocellular toxicity. Biochem. Pharmacol. 2016, 116, 153– 161, DOI: 10.1016/j.bcp.2016.07.007[Crossref], [PubMed], [CAS], Google Scholar129https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtFyiu7bO&md5=b23ad627ac6478c8ba2ec987388bdc92Human arylacetamide deacetylase hydrolyzes ketoconazole to trigger hepatocellular toxicityFukami, Tatsuki; Iida, Azumi; Konishi, Keigo; Nakajima, MikiBiochemical Pharmacology (Amsterdam, Netherlands) (2016), 116 (), 153-161CODEN: BCPCA6; ISSN:0006-2952. (Elsevier B.V.)Ketoconazole (KC), an antifungal agent, rarely causes severe liver injury when orally administered. It has been reported that KC is mainly hydrolyzed to N-deacetyl ketoconazole (DAK), followed by the N-hydroxylation of DAK by flavin-contg. monooxygenase (FMO). Although the metab. of KC has been considered to be assocd. with hepatotoxicity, the responsible enzyme(s) remain unknown. The purpose of this study was to identify the responsible enzyme(s) for KC hydrolysis in humans and to clarify their relevance to KC-induced toxicity. Kinetic anal. and inhibition studies using human liver microsomes (HLM) and recombinant enzymes revealed that human arylacetamide deacetylase (AADAC) is responsible for KC hydrolysis to form DAK, and confirmed that FMO3 is the enzyme responsible for DAK N-hydroxylation. In HLM, the clearance of KC hydrolysis occurred to the same extent as DAK N-hydroxylation, which indicates that both processes are not rate-limiting pathways. Cytotoxicity of KC and DAK was evaluated using HepaRG cells and human primary hepatocytes. Treatment of HepaRG cells with DAK for 24 h showed cytotoxicity in a dose-dependent manner, whereas treatment with KC did not show due to the low expression of AADAC. Overexpression of AADAC in HepaRG cells with an adenovirus expression system elicited the cytotoxicity of KC. Cytotoxicity of KC in human primary hepatocytes was attenuated by diisopropylfluorophosphate, an AADAC inhibitor. In conclusion, the present study demonstrated that human AADAC hydrolyzes KC to trigger hepatocellular toxicity.
- 130(a) Niwa, T.; Imagawa, Y.; Yamazaki, H. Drug interactions between nine antifungal agents and drugs metabolized by human cytochromes P450. Curr. Drug Metab. 2015, 15, 651– 679, DOI: 10.2174/1389200215666141125121511 .(b) Khojasteh, S. C.; Prabhu, S.; Kenny, J. R.; Halladay, J. S.; Lu, A. Y. H. Chemical inhibitors of cytochrome P450 isoforms in human liver microsomes: a re-evaluation of P450 isoform selectivity. Eur. J. Drug Metab. Pharmacokinet. 2011, 36, 1– 16, DOI: 10.1007/s13318-011-0024-2[Crossref], [PubMed], [CAS], Google Scholar130bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXisleqsbk%253D&md5=b33b9fd9e9f59f88ca4e5cb242ac0fb4Chemical inhibitors of cytochrome P450 isoforms in human liver microsomes: a re-evaluation of P450 isoform selectivityKhojasteh, Siamak Cyrus; Prabhu, Saileta; Kenny, Jane R.; Halladay, Jason S.; Lu, Anthony Y. H.European Journal of Drug Metabolism and Pharmacokinetics (2011), 36 (1), 1-16CODEN: EJDPD2; ISSN:0378-7966. (Springer France)A review. The majority of marketed small-mol. drugs undergo metab. by hepatic Cytochrome P 450 (CYP) enzymes (Rendic 2002). Since these enzymes metabolize a structurally diverse no. of drugs, metab.-based drug-drug interactions (DDIs) can potentially occur when multiple drugs are coadministered to patients. Thus, a careful in vitro assessment of the contribution of various CYP isoforms to the total metab. is important for predicting whether such DDIs might take place. One method of CYP phenotyping involves the use of potent and selective chem. inhibitors in human liver microsomal incubations in the presence of a test compd. The selectivity of such inhibitors plays a crit. role in deciphering the involvement of specific CYP isoforms. Here, we review published data on the potency and selectivity of chem. inhibitors of the major human hepatic CYP isoforms. The most selective inhibitors available are furafylline (in co-incubation and pre-incubation conditions) for CYP1A2, 2-phenyl-2-(1-piperidinyl)propane (PPP) for CYP2B6, montelukast for CYP2C8, sulfaphenazole for CYP2C9, (-)-N-3-benzyl-phenobarbital for CYP2C19 and quinidine for CYP2D6. As for CYP2A6, tranylcypromine is the most widely used inhibitor, but on the basis of initial studies, either (3-(pyridin-3-yl)-1H-pyrazol-5-yl)methanamine (PPM) and 3-(2-methyl-1H-imidazol-1-yl)pyridine (MIP) can replace tranylcypromine as the most selective CYP2A6 inhibitor. For CYP3A4, ketoconazole is widely used in phenotyping studies, although azamulin is a far more selective CYP3A inhibitor. Most of the phenotyping studies do not include CYP2E1, mostly because of the limited no. of new drug candidates that are metabolized by this enzyme. Among the inhibitors for this enzyme, 4-methylpyrazole appears to be selective.
- 131(a) Van Tyle, J. H. Ketoconazole; Mechanism of action, spectrum of activity, pharmacokinetics, drug interactions, adverse reactions and therapeutic use. Pharmacotherapy 1984, 4, 343– 373, DOI: 10.1002/j.1875-9114.1984.tb03398.x[Crossref], [PubMed], [CAS], Google Scholar.131ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL2M%252FovVWnsg%253D%253D&md5=b51d809c5dc7d7f01c7a268fbc776c22Ketoconazole. Mechanism of action, spectrum of activity, pharmacokinetics, drug interactions, adverse reactions and therapeutic useVan Tyle J HPharmacotherapy (1984), 4 (6), 343-73 ISSN:0277-0008.Ketoconazole is a well-tolerated oral antifungal agent with a broad spectrum of activity in vitro, but in vitro testing has not yet been correlated to in vivo results. In addition, many variables that can alter in vitro test results have been identified. The drug shows effectiveness in the treatment of paracoccidioidomycosis, chronic mucocutaneous candidiasis, oral thrush, coccidioidomycosis and histoplasmosis. It was recently approved for use in blastomycosis. It is not yet approved for use in dermatophyte infections, but a large body of literature exists supporting this application. Ketoconazole has several reported drug interactions, including lower bioavailability with cimetidine, accumulation of cyclosporin during concurrent therapy and a possible disulfiram-like reaction with alcohol. It is highly protein bound to albumin and is extensively metabolized. Dosage adjustment is not required in renal failure. The main side effects are gastrointestinal and occur in 5-10% of the patients. Rare side effects include gynecomastia and hepatotoxicity. The latter is reported to occur in 1 of 12,000 patients. Ketoconazole impairs testosterone synthesis, and therefore it is recommended that administration more than once daily be avoided in men. The usual dosage is 200-400 mg administered once daily. Few comparative or controlled studies have been published thus far. How it compares to amphotericin B is not known. The optimum dosage and the optimum duration of therapy are not established.(b) Rodriguez, R. J.; Acosta, D., Jr. Metabolism of ketoconazole and deacetylated ketoconazole by rat hepatic microsomes and flavin-containing monooxygenases. Drug Metab. Dispos. 1997, 25, 772– 777[PubMed], [CAS], Google Scholar131bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXktFGnsr0%253D&md5=24a271ccf1450134bd59216602676544Metabolism of ketoconazole and deacetylated ketoconazole by rat hepatic microsomes and flavin-containing monooxygenasesRodriguez, Rosita J.; Acosta, Daniel, Jr.Drug Metabolism and Disposition (1997), 25 (6), 772-777CODEN: DMDSAI; ISSN:0090-9556. (Williams & Wilkins)Ketoconazole (KT) has been reported to cause hepatotoxicity, which is probably not mediated through an immunoallergic mechanism. Although KT is extensively metabolized by hepatic microsomal enzymes, the nature, route of formation, and toxicity suspected metabolites are largely unknown. Recent reports indicate that N-deacetyl ketoconazole (DAK) is a major initial metabolite in mice, which, like lipophilic-4-alkylpiperazines, is susceptible to successive oxidative attacks on the N-1 position producing ring-opened dialdehydes. The rate of formation of DAK from hepatic rat microsomal incubations of KT was detd. by HPLC. The rate of disappearance for KT was almost equal to the rate of DAK formation: 5.96 and 5.88 μM/h, resp. Also, the potential bioactivation of DAK was evaluation by measuring substrate activity of DAK with purified pig liver flavin-contg. monooxygenase (FMO) and rat liver microsomes. Activity was measured by following DAK-dependent oxygen uptake polarog. at 37°C in pyrophosphate buffer (pH 8.8) contg. the glucose-6-phosphate NADPH-generating system. The KM's of DAK were 34.6 and 77.4 μM for the purified FMO and rat microsomal FMO, resp. Lastly, DAK was found to be metabolized by an NADPH-dependent rat liver microsomal monooxygenases at pH 8.8 to two metabolites as detd. by HPLC. Heat inactivation of rat liver microsomal FMO abolished the formation of these metabolites from DAK. SKF-525A and anti-rat NADPH cytochrome P 450 reductase did not inhibit this reaction. These results suggest that deacetylation of KT yields a major product, DAK, for further metab. by microsomal monooxygenases that seem to be FMO-related.
- 132(a) Poirier, J. M.; Lebot, M.; Descamps, P.; Levy, M.; Cheymol, G. Determination of itraconazole and its active metabolite in plasma by column liquid chromatography. Ther. Drug Monit. 1994, 16, 596– 601, DOI: 10.1097/00007691-199412000-00011[Crossref], [PubMed], [CAS], Google Scholar.132ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXivVKjtr0%253D&md5=e12bb84ab00e418e53d338e921494904Determination of itraconazole and its active metabolite in plasma by column liquid chromatographyPoirier, Jean-Marie; Lebot, Martine; Descamps, Philippe; Levy, Monique; Cheymol, GeorgesTherapeutic Drug Monitoring (1994), 16 (6), 596-601CODEN: TDMODV; ISSN:0163-4356.Oral itraconazole is effective against a wide range of fungal pathogens that includes Aspergillus species, and its use in leukemic and AIDS patients is currently on the increase. Itraconazole undergoes extensive metab. and the main isolated metabolite, hydroxyitraconazole, is found in plasma at concns. 2-3-fold higher than parent drug and presents in vitro the same antifungal activity. At present, despite the contribution of this metabolite to the overall activity of the drug, no well-documented assay was reported in the literature for the simultaneous detn. of itraconazole and hydroxyitraconazole in plasma. Due to the wide variety of coadministered drugs to patients receiving itraconazole, the purpose of the developed method was to obtain a specific assay sensitive enough for itraconazole therapeutic monitoring. Therefore, a 3-step liq.-liq. extn. procedure followed by reversed-phase HPLC and spectrofluorimetric detection was performed. This assay allowed detn. of 20 ng/mL of both itraconazole and its active metabolite with an acceptable precision using a 0.5-mL plasma sample; no analytic interference was encountered from 45 coadministered drugs tested.(b) Peng, C. C.; Shi, W.; Lutz, J. D.; Kunze, K. L.; Liu, J. O.; Nelson, W. L.; Isoherranen, N. Stereospecific metabolism of itraconazole by CYP3A4: dioxolane ring scission of azole antifungals. Drug Metab. Dispos. 2012, 40, 426– 435, DOI: 10.1124/dmd.111.042739[Crossref], [PubMed], [CAS], Google Scholar132bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xjs1WqtLc%253D&md5=366d102f96b6d538a73cfab0eece23ceStereospecific metabolism of itraconazole by CYP3A4: dioxolane ring scission of azole antifungalsPeng, Chi-Chi; Shi, Wei; Lutz, Justin D.; Kunze, Kent L.; Liu, Jun O.; Nelson, Wendel L.; Isoherranen, NinaDrug Metabolism & Disposition (2012), 40 (3), 426-435CODEN: DMDSAI; ISSN:1521-009X. (American Society for Pharmacology and Experimental Therapeutics)Itraconazole (ITZ) is a mixt. of four cis-stereoisomers that inhibit CYP3A4 potently and coordinate CYP3A4 heme via the triazole nitrogen. However, (2R,4S,2'R)-ITZ and (2R,4S,2'S)-ITZ also undergo stereoselective sequential metab. by CYP3A4 at a site distant from the triazole ring to 3'-OH-ITZ, keto-ITZ, and N-desalkyl-ITZ. This stereoselective metab. demonstrates specific interactions of ITZ within the CYP3A4 active site. To further investigate this process, the binding and metab. of the four trans-ITZ stereoisomers by CYP3A4 were characterized. All four trans-ITZ stereoisomers were tight binding inhibitors of CYP3A4-mediated midazolam hydroxylation (IC50 16-26 nM), and each gave a type II spectrum upon binding to CYP3A4. However, instead of formation of 3'-OH-ITZ, they were oxidized at the dioxolane ring, leading to ring scission and formation of two new metabolites of ITZ. These two metabolites were also formed from the four cis-ITZ stereoisomers, although not as efficiently. The catalytic rates of dioxolane ring scission were similar to the dissocn. rates of ITZ stereoisomers from CYP3A4, suggesting that the heme iron is reduced while the triazole moiety coordinates to it and no dissocn. of ITZ is necessary before catalysis. The triazole contg. metabolite [1-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone] also inhibited CYP3A4 (IC50 >15 μM) and showed type II binding with CYP3A4. The dioxolane ring scission appears to be clin. relevant because this metabolite was detected in urine samples from subjects that had been administered the mixt. of cis-ITZ isomers. These data suggest that the dioxolane ring scission is a metabolic pathway for drugs that contain this moiety.
- 133(a) Sawyer, P. R.; Brogden, R. N.; Pinder, R. M.; Speight, T. M.; Avery, G. S. Miconazole: review of its antifungal activity and therapeutic efficacy. Drugs 1975, 9, 406– 423, DOI: 10.2165/00003495-197509060-00002[Crossref], [PubMed], [CAS], Google Scholar.133ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE2MXlslahtLk%253D&md5=450bfc9d39bf0f4f1b6f9bc80197a22bMiconazole. Review of its antifungal activity and therapeutic efficacySawyer, Phyllis R.; Brogden, R. N.; Pinder, R. M.; Speight, T. M.; Avery, G. S.Drugs (1975), 9 (6), 406-23CODEN: DRUGAY; ISSN:0012-6667.A review of the pharmacol. of miconazole nitrate (I) [22832-87-7]; 30 refs.(b) Fothergill, A. W. Miconazole: a historical perspective. Expert Rev. Anti-Infect. Ther. 2006, 4, 171– 175, DOI: 10.1586/14787210.4.2.171[Crossref], [PubMed], [CAS], Google Scholar133bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XktVSjsLc%253D&md5=9d7d813082801dc577c65ede0ff6b1f4Miconazole: a historical perspectiveFothergill, Annette W.Expert Review of Anti-Infective Therapy (2006), 4 (2), 171-175CODEN: ERATCK; ISSN:1478-7210. (Future Drugs Ltd.)A review. Miconazole is an imidazole that has been successfully used for over 30 years for the treatment of superficial and cutaneous disease. This agent is distinguished from other azoles by possessing two mechanisms of action. The first mechanism is shared with other azoles and involves the inhibition of ergosterol synthesis. Another mechanism involves inhibition of peroxidases, which results in the accumulation of peroxide within the cell resulting in cell death. Susceptibility patterns for miconazole demonstrate that yeast fungi remain largely susceptible even in light of repeated exposures. Despite the release of newer azoles and other classes of antifungals, miconazole remains a highly prescribed treatment for vaginal candidiasis.
- 134Godefroi, E. F.; Heeres, J.; Van Cutsem, J.; Janssen, P. A. J. The preparation and antimycotic properties of derivatives of 1-phenethylimidazole. J. Med. Chem. 1969, 12, 784– 791, DOI: 10.1021/jm00305a014[ACS Full Text], [CAS], Google Scholar134https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF1MXltFartLw%253D&md5=2abc3cb646059f4af1147cff78a19630Preparation and antimycotic properties of derivatives of 1-phenethylimidazoleGodefroi, Erik F.; Heeres, Jan; Van Cutsem, Jan; Janssen, Paul A. J.Journal of Medicinal Chemistry (1969), 12 (5), 784-91CODEN: JMCMAR; ISSN:0022-2623.The synthesis of a large no. of β-substituted-1-phenethylimidazoles is described. Many appropriately N-substituted-1-(β-aminophenethyl)imidazoles and cyclic ketals derived from 2-(1-imidazolyl)acetophenones were quite active against dermatophytes. However, 1-(β-benzyloxyphenethyl)-imidazoles displayed potent, broad-spectrum activity, not only against dermatophytes but also against yeast cells (Candida albicans) and gram-pos. bacteria.
- 135Heeres, J.; Van Cutsem, J. Antimycotic imidazoles. 5. Synthesis and antimycotic properties of 1-[[2-aryl-4-(arylalkyl)-1,3-dioxolan-2-yl]methyl]-1H-imidazoles. J. Med. Chem. 1981, 24, 1360– 1364, DOI: 10.1021/jm00143a019[ACS Full Text], [CAS], Google Scholar135https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL3MXls1Wktb4%253D&md5=ff28d3f4257300c6f76ced0a6069db9eAntimycotic imidazoles. 5. Synthesis and antimycotic properties of 1-[[2-aryl-4-(arylalkyl)-1,3-dioxolan-2-yl]methyl]-1H-imidazolesHeeres, J.; Van Cutsem, J.Journal of Medicinal Chemistry (1981), 24 (11), 1360-4CODEN: JMCMAR; ISSN:0022-2623.Forty title compds. I (R and R1 = H, Cl, Br, or Me; R2 and R3 = H, Br, Cl, OMe, Ph, etc.; n = 0-2) were synthesized and tested in vivo and in vitro for antifungal and antibacterial activities. Most of the compds. had high in vitro activity against dermatophytes comparable to miconazole. Some compds. were also active against yeasts, other fungi, and gram-pos. bacteria, but they had no activity against gram-neg. bacteria. Alkyl chain length had only minor effects on in vitro activity.
- 136Heeres, J.; Meerpoel, L.; Lewi, P. Conazoles. Molecules 2010, 15, 4129– 4188, DOI: 10.3390/molecules15064129[Crossref], [PubMed], [CAS], Google Scholar136https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXns1KktrY%253D&md5=15947d5d12b9eabe58e87ffa4db15f65ConazolesHeeres, Jan; Meerpoel, Lieven; Lewi, PaulMolecules (2010), 15 (), 4129-4188CODEN: MOLEFW; ISSN:1420-3049. (Molecular Diversity Preservation International)A review. This review provides a historical overview of the analog based drug discovery of miconazole and its congeners, and is focused on marketed azole antifungals bearing the generic suffix "conazole". The antifungal activity of miconazole, one of the first broad-spectrum antimycotic agents has been mainly restricted to topical applications. The attractive in vitro antifungal spectrum was a starting point to design more potent and esp. orally active antifungal agents such as ketoconazole, itraconazole, posaconazole, fluconazole and voriconazole. The chem., in vitro and in vivo antifungal activity, pharmacol., and clin. applications of these marketed conazoles has been described.
- 137Lewis, D. F.; Wiseman, A.; Tarbit, M. H. Molecular modelling of lanosterol 14α-demethylase (CYP51) from Saccharomyces cerevisiae via homology with CYP102, a unique bacterial cytochrome P450 isoform: quantitative structure-activity relationships (QSARs) within two related series of antifungal azole derivatives. J. Enzyme Inhib. 1999, 14, 175– 192, DOI: 10.3109/14756369909030315[Crossref], [PubMed], [CAS], Google Scholar137https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXotFelu7g%253D&md5=02085aee59458f9b17734ec6f4b492cdMolecular modelling of lanosterol 14α-demethylase (CYP51) from Saccharomyces cerevisiae via homology with CYP102, a unique bacterial cytochrome P450 isoform: quantitative structure-activity relationships (QSARs) within two related series of antifungal azole derivativesLewis, David F. V.; Wiseman, Alan; Tarbit, Mike H.Journal of Enzyme Inhibition (1999), 14 (3), 175-192CODEN: ENINEG; ISSN:8755-5093. (Harwood Academic Publishers)The construction of a three-dimensional mol. model of the fungal form of cytochrome P 450 (CYP51) from Saccharomyces cerevisiae, based on homol. with the hemoprotein domain of CYP102 from Bacillus megaterium (a unique bacterial P 450 of known crystal structure) is described. It is found that the endogenous substrate, lanosterol, can readily occupy the putative active site of the CYP51 model such that the known mono-oxygenation reaction, leading to C14-demethylation of lanosterol, is the preferred route of metab. for this particular substrate. Key amino acid contacts within the CYP51 active site appear to orientate lanosterol for oxidative attack at the C14-Me group, and the position of the substrate relative to the hem moiety is consistent with the phenyl-iron complexation studies reported by Tuck et al. Typical azole inhibitors, such as ketoconazole, are able to fit the putative active site of CYP51 by a combination of hem ligation, hydrogen bonding, π-π stacking and hydrophobic interactions within the enzyme's hem environment. The mode of action of azole antifungals, as described by the modeling studies, is supported by quant. structure-activity relationship (QSAR) analyses on two groups of structurally related fungal inhibitors. Moreover, the results of mol. electrostatic isopotential (EIP) energy calcns. are compatible with the proposed mode of binding between azole antifungal agents and the putative active site of CYP51, although membrane interactions may also have a role in the antifungal activity of azole derivs.
- 138(a) Collis, A. J.; Foster, M. L.; Halley, F.; Maslen, C.; McLay, I. M.; Page, K. M.; Redford, E. J.; Souness, J. E.; Wilsher, N. E. RPR203494 a pyrimidine analogue of the p38 inhibitor RPR200765A with an improved in vitro potency. Bioorg. Med. Chem. Lett. 2001, 11, 693– 696, DOI: 10.1016/S0960-894X(01)00034-8[Crossref], [PubMed], [CAS], Google Scholar.138ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXhslOntrg%253D&md5=b4cc561166be1ffbef67596b6d469717RPR203494 a pyrimidine analogue of the p38 inhibitor RPR200765A with an improved in vitro potencyCollis, Alan J.; Foster, Martyn L.; Halley, Frank; Maslen, Christopher; McLay, Iain M.; Page, Kenneth M.; Redford, E. Jane; Souness, John E.; Wilsher, Nicola E.Bioorganic & Medicinal Chemistry Letters (2001), 11 (5), 693-696CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)Following the discovery of RPR200765, a series of pyrimidine analogs have been prepd. as backups. Amongst them, RPR203494 was identified with a better in vitro profile than RPR200765A.(b) McKenna, J. M.; Halley, F.; Souness, J. E.; McLay, I. M.; Pickett, S. D.; Collis, A. J.; Page, K.; Ahmed, I. An algorithm-directed two-component library synthesized via solid-phase methodology yielding potent and orally bioavailable p38 MAP kinase inhibitors. J. Med. Chem. 2002, 45, 2173– 2184, DOI: 10.1021/jm011132l[ACS Full Text], [CAS], Google Scholar138bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XjtFGmtLo%253D&md5=28a03ae9b698df7cd154141127069352An Algorithm-Directed Two-Component Library Synthesized Via Solid-Phase Methodology Yielding Potent and Orally Bioavailable p38 MAP Kinase InhibitorsMcKenna, Jeffrey M.; Halley, Frank; Souness, John E.; McLay, Iain M.; Pickett, Stephen D.; Collis, Alan J.; Page, Kenneth; Ahmed, ImtiazJournal of Medicinal Chemistry (2002), 45 (11), 2173-2184CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Previously we reported the identification of RPR200765A, a potent orally bioavailable pyridine-imidazole inhibitor of p38 mitogen-activated protein (MAP) kinase which suppressed paw swelling and joint pathol. in streptococcal cell wall-induced arthritis. Herein, we report the use of solid-phase combinatorial org. synthesis for the parallel processing of a related pyrimidine-imidazole-based library with two points of structural variability. We report also that the application of a computer algorithm, the Monte Carlo Monomer Selection, maximized both the combinatorial synthetic efficiency and the bioavailability of the final compds. In conjunction with the synthetic protocols, the polymer-supported quench technique was applied to the purifn. of the final compds. Through rapid evaluation of the library using a p38 kinase assay and permeability assays, it was possible to identify a no. of potent and orally bioavailable p38 MAP kinase inhibitors suitable for further biol. investigation.
- 139(a) Abbotto, A.; Bradamante, S.; Pagani, G. A. Diheteroarylmethanes. 5.1 E-Z isomerism of carbanions substituted by 1,3-azoles: 13C and 15N δ-charge/shift relationships as source for mapping charge and ranking the electron-withdrawing power of heterocycles. J. Org. Chem. 1996, 61, 1761– 1769, DOI: 10.1021/jo951884l[ACS Full Text.], [CAS], Google Scholar139ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XhtFersb8%253D&md5=11ce86914febca0b3e37daa0bea80e29Diheteroarylmethanes. 5. E-Z Isomerism of Carbanions Substituted by 1,3-Azoles: 13C and 15N π-Charge/Shift Relationships as Source for Mapping Charge and Ranking the Electron-Withdrawing Power of HeterocyclesAbbotto, Alessandro; Bradamante, Silvia; Pagani, Giorgio A.Journal of Organic Chemistry (1996), 61 (5), 1761-9CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)Previously proposed π-charge/shift relationships have been applied to 13C and 15N shifts of the carbanions of 2-benzylazoles (thiazole, oxazole, and imidazole), their corresponding benzo-fused analogs, and bis(2-azolyl)methanes (azolyl groups as above). In this way it is possible to rank the π electron-withdrawing power of these heterocycles in terms of charge demands cX, a quantity representing the fraction of π neg. charge withdrawn (delocalized) by the ring. The results indicate that cthiaz > coxaz > cimidaz; furthermore, benzo azoles are more efficient than monocyclic systems in delocalizing the neg. charge. The charge demand cX of imidazole is the smallest among the heteroaroms. so far considered, being even smaller than that of the Ph ring. As a consequence, the neg. charge in the anion of 2-benzyl-N-methylimidazole is predominantly transferred from the carbanionic carbon to the Ph group rather than to the imidazolyl residue.The high double bond character of the bond linking the carbanionic and ipso Ph ring carbons leads to room temp. 13C shift anisochrony of the meta and meta' and ortho and ortho' positions of the Ph ring. In all of the other cases, hindered rotation is obsd. at room temp. between the carbanionic carbon and position 2 of the heterocycle. A single set of resonances is presented by the bis(heteroaryl)methyl carbanions. π-Charge/shift relationships allow for the accurate π-charge mapping in these carbanionic systems, and the results point to considerable delocalization of the electron pair(s) of the oxygen and pyrrolic nitrogen atoms at position 1 in oxazole and imidazole toward the pyridic nitrogen at position 3 of the rings (in both the neutrals and the carbanionic species). On the contrary, not only does the sulfur atom in thiazole derivs. not delocalize any neg. charge in the anions but it is barely involved in any π-donation to the pyridic nitrogen atom at position 3 also in the neutrals.(b) Abbotto, A.; Bradamante, S.; Facchetti, A.; Pagani, G. A. Metal chelation aptitudes of bis(o-azaheteroaryl)methanes as tuned by heterocycle charge demands. J. Org. Chem. 2002, 67, 5753– 5772, DOI: 10.1021/jo025696o[ACS Full Text], [CAS], Google Scholar139bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XltFGmtrg%253D&md5=2ff6ed169d69cc8c5e39a5f251397310Metal Chelation Aptitudes of Bis(o-azaheteroaryl)methanes As Tuned by Heterocycle Charge DemandsAbbotto, Alessandro; Bradamante, Silvia; Facchetti, Antonio; Pagani, Giorgio A.Journal of Organic Chemistry (2002), 67 (16), 5753-5772CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)The authors describe the synthesis of a no. of 1,3-azol-2-yl-, 1,3-benzazol-2-yl-, and azinyl-based bis(o-azaheteroaryl)methanes (LH, L- = Het2CH-) and their coordinating properties toward divalent transition metals (Zn, Cu, Co, Ni, Hg, Pd). This extended study includes both sym. and unsym. ligands based on several substituted and/or unsubstituted thiazole, benzothiazole, benzoxazole, benzimidazole, pyridine, and quinoline derivs. Depending on the structure and electron properties of the ligand, a vast set of neutral chelates ML2 were obtained, where the ligand is present in its carbanionic form L-. Addnl., the authors prepd. salt complexes [M(LH)n]Xm, where the ligand is present as a neutral system. Neutral chelates were typically obtained by the reaction of the ligand with metal acetates in alc. soln. Salt complexes were formed by reaction with other metal salts such as chlorides. By exploring the coordinating properties of several bisheteroarylmethane ligands based on heteroaroms. of variable π-electron structure and substitution pattern, the formation of neutral chelates is strictly dependent on the electron-withdrawing capacity (charge demand) of the heteroarom. moiety. The latter primarily dictates the efficiency by which the neg. charge of the anionic ligand L- is stabilized by delocalization in ML2 and, therefore, the stability of the chelate itself. From the large no. and the variable nature of the N ligands used, the authors confirm the general validity of the charge-demand-dependent formation of chelates. This key factor can therefore be used for the efficient design of new π-deficient heteroarom. N ligands in chelates of great potential in many synthetic, catalytic, and technol. fields.
- 140Collis, A.; Halley, F.; McClay, I. Heteroaryl-cyclic acetals. U.S. Patent 7,479,501 B2. January 30th, 2009.
- 141(a) Lovering, F. Escape from flatland 2: complexity and promiscuity. MedChemComm 2013, 4, 515– 519, DOI: 10.1039/c2md20347b[Crossref], [CAS], Google Scholar.141ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjtFShtL0%253D&md5=c03d3b99da22a684cbbbb00fb1633342Escape from Flatland 2: complexity and promiscuityLovering, FrankMedChemComm (2013), 4 (3), 515-519CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)Toxicity plays a major role in attrition in the clinic and promiscuity has been linked to toxicity. A no. of mol. descriptors have been identified that contribute to promiscuity including ionization and logP. In this study we report on the relationship between complexity, as measured by two descriptors [fraction sp3 (Fsp3) where Fsp3 = (no. of sp3 hybridized carbons/total carbon count) and chiral carbon count], and promiscuity as well as Cyp450 inhibition. We find that increasing complexity reduces promiscuity and Cyp450 inhibition. As an understanding of key property descriptors has helped the pharmaceutical industry to address some of the deficiencies of compds. as pertains to bioavailability, awareness of the descriptors that impact promiscuity should allow us to better address toxicity in the clinic.(b) Clemons, P. A.; Bodycombe, N. E.; Carrinski, H. A.; Wilson, J. A.; Shamji, A. F.; Wagner, B. K.; Koehler, A. N.; Schreiber, S. L. Small molecules of different synthetic and natural origins have distinct distributions of structural complexity that correlate with protein binding profiles. Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 18787– 18792, DOI: 10.1073/pnas.1012741107[Crossref], [PubMed], [CAS], Google Scholar.141bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsVCqsb%252FN&md5=198e298ca5391d7dfd91184680e3c2ecSmall molecules of different origins have distinct distributions of structural complexity that correlate with protein-binding profilesClemons, Paul A.; Bodycombe, Nicole E.; Carrinski, Hyman A.; Wilson, J. Anthony; Shamji, Alykhan F.; Wagner, Bridget K.; Koehler, Angela N.; Schreiber, Stuart L.Proceedings of the National Academy of Sciences of the United States of America (2010), 107 (44), 18787-18792, S18787/1-S18787/5CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Using a diverse collection of small mols. generated from a variety of sources, we measured protein-binding activities of each individual compd. against each of 100 diverse (sequence-unrelated) proteins using small-mol. microarrays. We also analyzed structural features, including complexity, of the small mols. We found that compds. from different sources (com., academic, natural) have different protein-binding behaviors and that these behaviors correlate with general trends in stereochem. and shape descriptors for these compd. collections. Increasing the content of sp3-hybridized and stereogenic atoms relative to compds. from com. sources, which comprise the majority of current screening collections, improved binding selectivity and frequency. The results suggest structural features that synthetic chemists can target when synthesizing screening collections for biol. discovery. Because binding proteins selectively can be a key feature of high-value probes and drugs, synthesizing com- pounds having features identified in this study may result in improved performance of screening collections.(c) Meanwell, N. A. Improving drug design: an update on recent applications of efficiency metrics, strategies for replacing problematic elements, and compounds in nontraditional drug space. Chem. Res. Toxicol. 2016, 29, 564– 616, DOI: 10.1021/acs.chemrestox.6b00043[ACS Full Text], [CAS], Google Scholar141chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XktVCrs7Y%253D&md5=aef48399fb698b5f958c1cc11e1d25aaImproving Drug Design: An Update on Recent Applications of Efficiency Metrics, Strategies for Replacing Problematic Elements, and Compounds in Nontraditional Drug SpaceMeanwell, Nicholas A.Chemical Research in Toxicology (2016), 29 (4), 564-616CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)Drug discovery and development is a complex and lengthy enterprise that suffers from high rates of candidate attrition at all stages of the process. The phys., biol., and toxicol. properties of a drug candidate are inextricably linked to its structure, and once a mol. has been synthesized, all subsequent studies along the development path are focused only on assessing and understanding its properties in greater detail. Unfortunately, a full prediction of the biol. properties of a mol. from an anal. of its 2- or 3-dimensional structure is currently beyond our expertise. This backdrop mandates that considerable care be taken at the design stage if a mol. is to be successful in testing a mechanistic concept underlying a disease process and to progress into late stage clin. trials and, ultimately, marketing approval. While there are multiple potential causes of candidate attrition, an introspective anal. of drug design practices over the past decade has focused attention on the perception that contemporary mols. are unnecessarily obese, burdened by high mol. wt. and excessive lipophilicity. This practice is believed to have its roots in the singular pursuit of enhancing potency during lead optimization rather than adopting a more holistic approach to drug design that gives broader consideration to how structural features affect developability properties. In an effort to provide the medicinal chem. community with practical guideposts to enhancing compd. quality in the drug design phase and which can readily be applied, a series of efficiency indexes have been proposed that attempt to define aspects of compd. quality in the context of a series of physicochem. parameters. Of these metrics, lipophilic ligand efficiency (LLE or LipE), which provides an index of the dependence of the potency of a mol. on its intrinsic lipophilicity, has been characterized as the most robust metric that has potential for broad-based application. In this review, after describing the background literature behind the derivation of efficiency metrics and approaches to assessing compd. aesthetics, synopses of some recent practical application in lead optimization campaigns are presented. However, mols. that fall into space beyond that assocd. with traditional drug-like properties are an important part of the current and future landscape, exemplified by the summary of direct acting hepatitis C virus NS3 and NS5A inhibitors that have transformed clin. therapy for this chronic disease. While drug development in nontraditional drug-like space is more challenging and the rules for compd. quality will be different with much still to be understood, careful and disciplined drug design practices will be an essential element of success.
- 142Astles, P. C.; Ashton, M. J.; Bridge, A. W.; Harris, N. V.; Hart, T. W.; Parrott, D. P.; Porter, B.; Riddell, D.; Smith, C.; Williams, R. J. Acyl-CoA:cholesterol O-acyltransferase (ACAT) inhibitors. 2. 2-(1,3-Dioxan-2-yl)-4,5-diphenyl-1H-imidazoles as potent inhibitors of ACAT. J. Med. Chem. 1996, 39, 1423– 1432, DOI: 10.1021/jm9505876[ACS Full Text], [CAS], Google Scholar142https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XhsVyht7w%253D&md5=1ceb0a60072c774e83ee359dd4fb128bAcyl-CoA:cholesterol O-acyltransferase (ACAT) inhibitors. 2. 2-(1,3-Dioxan-2-yl)-4,5-diphenyl-1H-imidazoles as potent inhibitors of ACATAstles, Peter C.; Ashton, Michael J.; Bridge, Andrew W.; Harris, Neil V.; Hart, Terrance W.; Parrott, David P.; Porter, Barry; Riddell, David; Smith, Christopher; Williams, Robert J.Journal of Medicinal Chemistry (1996), 39 (7), 1423-32CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The second in this series of papers concerns the further investigations into the search for a potent bioavailable acyl-CoA:cholesterol O-acyltransferase (ACAT) inhibitor suitable for the treatment of atherosclerosis. The design, synthesis, and structure-activity relation for a series of ACAT inhibitors based on the 2-(1,3-dioxan-2-yl)-4,5-diphenyl-1H-imidazole pharmacophore are described. Compds. bearing simple alkyl or hydroxymethyl substituents at the 5-position of the 1,3-dioxane ring are potent bioavailable inhibitors of the rat hepatic microsomal enzyme in vitro (IC50 < 100 nM) but are only weak inhibitors of the human hepatic enzyme. The authors have found however that 1,3-dioxanes substituted at the 5-cis position with pyrazolylalkyl or aminoalkyl groups are potent inhibitors in vitro of human macrophage ACAT, the potency depending on the nature of the terminal heterocycle and the length of the alkyl chain. An ex vivo bioassay described herein demonstrates that potent inhibitors which contain lipophilic terminal heterocycles do not appear to be systemically available. Less potent but more water sol. compds. are absorbed following oral dosing and achieve plasma levels significantly in excess of their IC50 for ACAT inhibition. These compds. are therefore possible candidates for further investigation as oral antiatherosclerotic agents.
- 143(a) Dostertp, P.; Langlois, M.; Guerret, P.; Ancher, J. F.; Bucher, B.; Mocquet, G. Synthesis and pharmacological properties of analogues of oxapadol, a new analgesic agent. Eur. J. Med. Chem. 1980, 15, 199– 205.(b) Mocquet, G.; Coston, A.; Jalfre, M. Animal pharmacology of oxapadol (MD 720111), a new non-narcotic analgesic. Experientia 1980, 36, 96– 97, DOI: 10.1007/BF02003996[Crossref], [PubMed], [CAS], Google Scholar143bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL3cXht1Wrt7k%253D&md5=358431582af3cdb84e3b3b19df67a58eAnimal pharmacology of oxapadol (MD 720111), a new non-narcotic analgesicMocquet, G.; Coston, A.; Jalfre, M.Experientia (1980), 36 (1), 96-7CODEN: EXPEAM; ISSN:0014-4754.In 4 species oxapadol (I) [56969-22-3] had analgesic activity similar to that of other nonnarcotic ref. analgesics. It also had antipyretic and antiinflammatory effects, and in the analgesic dose range I was devoid of undesirable neurol., gastro-intestinal, and cardiovascular side-effects.
- 144(a) Boureau, F.; Laquais, B.; Vadrot, M.; Willer, J.-C. Human neuropharmacological findings with oxapadol (MD 720111), a new non-narcotic analgesic. Experientia 1980, 36, 97– 98, DOI: 10.1007/BF02003997[Crossref], [PubMed], [CAS], Google Scholar.144ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL3cXhsVSltbc%253D&md5=215c1de2eb3d6793065974601ca069afHuman neuropharmacological findings with oxapadol (MD 720111) a new non-narcotic analgesicBoureau, F.; Laquais, B.; Vadrot, M.; Willer, J. C.Experientia (1980), 36 (1), 97-8CODEN: EXPEAM; ISSN:0014-4754.The effects of MD 720111 (oxapadol)(I) [56969-22-3], a new nonnarcotic analgesic, were tested in man using the elec.-induced nociceptive flexion reflex in the flexor muscles of the lower limb as an index of pain. The drug caused a significant increase in the threshold of the reflex whereas no change was noted with placebo.(b) Ancher, J. F.; Donath, A.; Malnoe, A.; Morizur, J. P.; Strolin Bekedetti, M. Urinary metabolites of oxapadol (MD720111), a new non-narcotic analgesic agent, in the rat, dog and man. Xenobiotica 1981, 11, 519– 530, DOI: 10.3109/00498258109045863[Crossref], [PubMed], [CAS], Google Scholar144bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL38XhtlGhs7g%253D&md5=7e7bdb17edd21622cca675c10ecb0b3aUrinary metabolites of oxapadol (MD720111), a new non-narcotic analgesic agent, in the rat, dog, and manAncher, J. F.; Donath, A.; Malnoe, A.; Morizur, J. P.; Strolin Benedetti, M.Xenobiotica (1981), 11 (8), 519-30CODEN: XENOBH; ISSN:0049-8254.A no. of metabolites of oxapadol (I) [56969-22-3] were isolated from rat, dog, and human urine after a single oral dose of I-14C, and were identified by direct inlet mass spectrometry and chromatog. comparison with ref. compds. I was extensively metabolized and unchanged I was not obsd. in rat or human urine, and only traces seen in dog urine. Nine metabolites were identified in rat and dog urine and 6 in man. The routes of biotransformation were arom. hydroxylation (mainly in the benzimidazole ring), scission of the heterocyclic ring following 2 different paths, and a combination of the two. Regioselectivity was obsd. for arom. hydroxylation as only 3 of the 4 possible monohydroxyoxazepinobenzimidazoles could be detected.
- 145Lenci, E.; Menchi, G.; Saldívar-Gonzalez, F.; Medina-Franco, J. L.; Trabocchi, A. Bicyclic acetals: biological relevance, scaffold analysis, and applications in diversity-oriented synthesis. Org. Biomol. Chem. 2019, 17, 1037– 1052, DOI: 10.1039/C8OB02808G[Crossref], [PubMed], [CAS], Google Scholar145https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisFCktLjE&md5=e7e98d22c9c6c239ec2722ed91166717Bicyclic acetals: biological relevance, scaffold analysis, and applications in diversity-oriented synthesisLenci, Elena; Menchi, Gloria; Saldivar-Gonzalez, Fernanda I.; Medina-Franco, Jose L.; Trabocchi, AndreaOrganic & Biomolecular Chemistry (2019), 17 (5), 1037-1052CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)A review. Natural products (NPs) have been shown to be an extraordinary source of bioactive compds. and three-dimensional complex frameworks that can be useful to produce high-value mol. collections that are able to address "undruggable" and difficult therapeutic targets. Bicyclic acetals are particularly relevant for these purposes, given their key role in several biol. interactions and the structural and stereochem. diversity that comes from the many possible ring combinations. To investigate this topol. diversity, we have systematically characterized in a systematic and detailed manner fused, spiro and bridged bicyclic acetals in a large set of NPs, highlighting the great potential of bicyclic acetals in Diversity-Oriented Synthesis (DOS). Accordingly, a summary of some recent efforts on the development of acetal-contg. small mol. collections through DOS approaches is herein reported.
- 146(a) Nomura, S.; Sakamaki, S.; Hongu, M.; Kawanishi, E.; Koga, Y.; Sakamoto, T.; Yamamoto, Y.; Ueta, K.; Kimata, H.; Nakayama, K.; Tsuda-Tsukimoto, M. Discovery of canagliflozin, a novel c-glucoside with thiophene ring, as sodium-dependent glucose co-transporter 2 inhibitor for the treatment of type 2 diabetes mellitus. J. Med. Chem. 2010, 53, 6355– 6360, DOI: 10.1021/jm100332n[ACS Full Text.], [CAS], Google Scholar146ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXpvVartbk%253D&md5=33c3a6bce5ae74799d051b6f8c06da7eDiscovery of Canagliflozin, a Novel C-Glucoside with Thiophene Ring, as Sodium-Dependent Glucose Co-transporter 2 Inhibitor for the Treatment of Type 2 Diabetes MellitusNomura, Sumihiro; Sakamaki, Shigeki; Hongu, Mitsuya; Kawanishi, Eiji; Koga, Yuichi; Sakamoto, Toshiaki; Yamamoto, Yasuo; Ueta, Kiichiro; Kimata, Hirotaka; Nakayama, Keiko; Tsuda-Tsukimoto, MinoruJournal of Medicinal Chemistry (2010), 53 (17), 6355-6360CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)We discovered that aryl C-glucosides, e.g. I, bearing a heteroarom. ring formed metabolically more stable inhibitors for sodium-dependent glucose co-transporter 2 (SGLT2). Thiophene I (canagliflozin) was a highly potent and selective SGLT2 inhibitor and showed pronounced anti-hyperglycemic effects in high-fat diet fed KK (HF-KK) mice.(b) Lamos, E. M.; Younk, L. M.; Davis, S. N. Canagliflozin, an inhibitor of sodium-glucose cotransporter 2, for the treatment of type 2 diabetes mellitus. Expert Opin. Drug Metab. Toxicol. 2013, 9, 763– 775, DOI: 10.1517/17425255.2013.791282[Crossref], [PubMed], [CAS], Google Scholar146bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXnsl2rtbw%253D&md5=b3fb9cc9c0bb8cd774ea19088c67481cCanagliflozin, an inhibitor of sodium-glucose cotransporter 2, for the treatment of type 2 diabetes mellitusLamos, Elizabeth M.; Younk, Lisa M.; Davis, Stephen N.Expert Opinion on Drug Metabolism & Toxicology (2013), 9 (6), 763-775CODEN: EODMAP; ISSN:1742-5255. (Informa Healthcare)A review. Introduction: is an orally administered sodium glucose cotransporter 2 inhibitor proposed for the treatment of type 2 diabetes. Canagliflozin improves glycemic control in an insulin-independent fashion through inhibition of glucose reuptake in the kidney. Areas covered: This article reviews the available data on the pharmacodynamics, the pharmacokinetics and metab., and the efficacy and safety of canagliflozin. Relevant articles were identified via PubMed using the search term canagliflozin with no date restriction. The authors also discuss the abstrs. from canagliflozin studies presented at large diabetes conferences. Expert opinion: Canagliflozin offers a relatively modest redn. in HbA1c, FPG, and PPG. It has a low incidence of hypoglycemia and a redn. in body wt. Dose adjustment may be recommended in the elderly, those on loop diuretics, and those with an estd. glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 if there are concerns or symptoms of vol.-related side effects. Issues remain with obsd. increases in low-d. lipoprotein cholesterol (LDL-C) and the odds of heart attack and stroke. Canagliflozin offers a novel mechanism of action, a modest glycemic control, and a favorable side-effect profile. It was approved by the US Food and Drug Administration in Apr. 2013 and is undergoing evaluation by the European Medicines Agency.
- 147(a) Meng, W.; Ellsworth, B. A.; Nirschl, A. A.; McCann, P. J.; Patel, M.; Girotra, R. N.; Wu, G.; Sher, P. M.; Morrison, E. P.; Biller, S. A.; Zahler, R. A.; Deshpande, P. P.; Pullockaran, A.; Hagan, D. L.; Morgan, N.; Taylor, J. R.; Obermeier, M. T.; Humphreys, W. G.; Khanna, A.; Discenza, L.; Robertson, J. G.; Wang, A.; Han, S.; Wetterau, J. R.; Janovitz, E. B.; Flint, O. P.; Whaley, J. M.; Washburn, W. N. Discovery of dapagliflozin: a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes. J. Med. Chem. 2008, 51, 1145– 1149, DOI: 10.1021/jm701272q[ACS Full Text.], [CAS], Google Scholar147ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhvFWgtrY%253D&md5=8b31ec17acef23a7507ce6a7d9184eb9Discovery of Dapagliflozin: A Potent, Selective Renal Sodium-Dependent Glucose Cotransporter 2 (SGLT2) Inhibitor for the Treatment of Type 2 DiabetesMeng, Wei; Ellsworth, Bruce A.; Nirschl, Alexandra A.; McCann, Peggy J.; Patel, Manorama; Girotra, Ravindar N.; Wu, Gang; Sher, Philip M.; Morrison, Eamonn P.; Biller, Scott A.; Zahler, Robert; Deshpande, Prashant P.; Pullockaran, Annie; Hagan, Deborah L.; Morgan, Nathan; Taylor, Joseph R.; Obermeier, Mary T.; Humphreys, William G.; Khanna, Ashish; Discenza, Lorell; Robertson, James G.; Wang, Aiying; Han, Songping; Wetterau, John R.; Janovitz, Evan B.; Flint, Oliver P.; Whaley, Jean M.; Washburn, William N.Journal of Medicinal Chemistry (2008), 51 (5), 1145-1149CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The C-aryl glucoside 6 (dapagliflozin) was identified as a potent and selective hSGLT2 inhibitor which reduced blood glucose levels in a dose-dependent manner by as much as 55% in hyperglycemic streptozotocin (STZ) rats. These findings, combined with a favorable ADME profile, have prompted clin. evaluation of dapagliflozin for the treatment of type 2 diabetes.(b) Plosker, G. L. Dapagliflozin: a review of its use in type 2 diabetes mellitus. Drugs 2012, 72, 2289– 2312, DOI: 10.2165/11209910-000000000-00000[Crossref], [PubMed], [CAS], Google Scholar147bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXovVChsg%253D%253D&md5=16042d47f6a1ffabafcde175fb5ca83cDapagliflozin: a review of its use in type 2 diabetes mellitusPlosker, Greg L.Drugs (2012), 72 (17), 2289-2312CODEN: DRUGAY; ISSN:0012-6667. (Adis Data Information BV)A review. Dapagliflozin (Forxiga) is the first in a novel class of glucose-lowering agents known as sodium-glucose co-transporter-2 (SGLT2) inhibitors and is used in the treatment of patients with type 2 diabetes. By inhibiting the transporter protein SGLT2 in the kidneys, dapagliflozin reduces renal glucose reabsorption, leading to urinary glucose excretion and a redn. in blood glucose levels. Unlike oral antidiabetic drugs from several other classes, the efficacy of dapagliflozin is independent of insulin secretion and action. Therefore, when used in combination with other antidiabetic drugs, dapagliflozin provides complementary therapy via its unique mechanism of action. A consistent finding across phase III, randomized, double-blind trials in patients with inadequately controlled type 2 diabetes was that dapagliflozin 5 or 10 mg/day for 24 wk as monotherapy in previously untreated patients, or as add-on combination therapy with metformin, glimepiride, pioglitazone or insulin-based therapy, significantly reduced both glycosylated Hb values (primary endpoint) and fasting plasma glucose levels compared with placebo. Various randomized trials have also shown improvements in postprandial blood glucose with dapagliflozin monotherapy and combination therapy compared with placebo. In addn., dapagliflozin was noninferior to glipizide, in terms of glycemic control after 52 wk, when used as add-on therapy in patients with type 2 diabetes that was inadequately controlled with metformin. In most clin. trials, dapagliflozin was assocd. with redns. in body wt. that were statistically superior to placebo or active comparators. Longer-term extension studies indicate that the efficacy of dapagliflozin is maintained for up to ≈2 years. Dapagliflozin was generally well tolerated in clin. trials of 24 or 52 wk duration and in extension studies of up to ≈2 years. Events suggestive of genital infections and urinary tract infections occurred more frequently among dapagliflozin than placebo recipients. These adverse events are of special interest because they appear to be related to the mechanism of action of dapagliflozin. Dapagliflozin has a low propensity to cause hypoglycemia, esp. when used alone or in combination with metformin, although the incidence of hypoglycemic events reported with dapagliflozin in clin. trials varied depending on the background therapy. Longer-term tolerability/safety data with dapagliflozin are awaited with interest. In conclusion, dapagliflozin, with its unique and complementary mechanism of action, appears to be an important addn. to the therapeutic options for the management of type 2 diabetes, particularly when used as add-on therapy.
- 148Haider, K.; Pathak, A.; Rohilla, A.; Haider, M. R.; Ahmad, K.; Yar, M. S. Synthetic strategy and SAR studies of C-glucoside heteroaryls as SGLT2 inhibitor: a review. Eur. J. Med. Chem. 2019, 184, 111773, DOI: 10.1016/j.ejmech.2019.111773[Crossref], [PubMed], [CAS], Google Scholar148https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvF2rt7bI&md5=4a0504769deefe13bdc3665809c8f7fbSynthetic strategy and SAR studies of C-glucoside heteroaryls as SGLT2 inhibitor: A reviewHaider, Kashif; Pathak, Ankita; Rohilla, Ankit; Haider, Md Rafi; Ahmad, Kamal; Yar, M. ShaharEuropean Journal of Medicinal Chemistry (2019), 184 (), 111773CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)A review with refs. Gliflozins constitute an important class of compds. useful as sodium glucose co-transporter (SGLT2) inhibitors to treat type-II diabetes. They act by blocking sodium-glucose transport protein 2 which is responsible for re-absorption of glucose in the proximal convoluted tubule (PCT) of kidney and thus its inhibition reduces blood glucose level. There are a no. of gliflozins which have been approved by drug regulatory bodies like FDA, EMA and PMDA whereas some others are in pipeline in their late developmental phases. The present review article offers a detailed account of synthetic strategies employed for the synthesis, alternate synthetic routes along with Structure Activity Relationship (SAR) studies of well-established as well as newly developed SGLT2 inhibitors.
- 149(a) Mascitti, V.; Maurer, T. S.; Robinson, R. P.; Bian, J.; Boustany-Kari, C. M.; Brandt, T.; Collman, B. M.; Kalgutkar, A. S.; Klenotic, M. K.; Leininger, M. T.; Lowe, A.; Maguire, R. J.; Masterson, V. M.; Miao, Z.; Mukaiyama, E.; Patel, J. D.; Pettersen, J. C.; Preville, C.; Samas, B.; She, L.; Sobol, Z.; Steppan, C. M.; Stevens, B. D.; Thuma, B. A.; Tugnait, M.; Zeng, D.; Zhu, T. Discovery of a clinical candidate from the structurally unique dioxa-bicyclo[3.2.1]octane class of sodium-dependent glucose cotransporter 2 inhibitors. J. Med. Chem. 2011, 54, 2952– 2960, DOI: 10.1021/jm200049r[ACS Full Text.], [CAS], Google Scholar149ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXktVCntrY%253D&md5=80e156d19d3a6a87a61dca59cc1a0e99Discovery of a Clinical Candidate from the Structurally Unique Dioxa-bicyclo[3.2.1]octane Class of Sodium-Dependent Glucose Cotransporter 2 InhibitorsMascitti, Vincent; Maurer, Tristan S.; Robinson, Ralph P.; Bian, Jianwei; Boustany-Kari, Carine M.; Brandt, Thomas; Collman, Benjamin M.; Kalgutkar, Amit S.; Klenotic, Michelle K.; Leininger, Michael T.; Lowe, Andre; Maguire, Robert J.; Masterson, Victoria M.; Miao, Zhuang; Mukaiyama, Emi; Patel, Jigna D.; Pettersen, John C.; Preville, Cathy; Samas, Brian; She, Li; Sobol, Zhanna; Steppan, Claire M.; Stevens, Benjamin D.; Thuma, Benjamin A.; Tugnait, Meera; Zeng, Dongxiang; Zhu, TongJournal of Medicinal Chemistry (2011), 54 (8), 2952-2960CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)PF-04971729 (I) belongs to a new class of potent and selective sodium-dependent glucose cotransporter 2 inhibitors incorporating a unique dioxa-bicyclo[3.2.1]octane (bridged ketal) ring system. In this paper we present the design, synthesis, preclin. evaluation, and human dose predictions related to I. This compd. demonstrated robust urinary glucose excretion in rats and an excellent preclin. safety profile. It is currently in phase 2 clin. trials and is being evaluated for the treatment of type 2 diabetes.(b) Mascitti, V.; Thuma, B. A.; Smith, A. C.; Robinson, R. P.; Brandt, T.; Kalgutkar, A. S.; Maurer, T. S.; Samas, B.; Sharma, R. On the importance of synthetic organic chemistry in drug discovery: reflections on the discovery of antidiabetic agent ertugliflozin. MedChemComm 2013, 4, 101– 111, DOI: 10.1039/C2MD20163A[Crossref], [CAS], Google Scholar149bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvVymsr%252FF&md5=49ad83c03fb27a8d5c5824e23864b24bOn the importance of synthetic organic chemistry in drug discovery: reflections on the discovery of antidiabetic agent ertugliflozinMascitti, Vincent; Thuma, Benjamin A.; Smith, Aaron C.; Robinson, Ralph P.; Brandt, Thomas; Kalgutkar, Amit S.; Maurer, Tristan S.; Samas, Brian; Sharma, RamanMedChemComm (2013), 4 (1), 101-111CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)A review. The discovery of antidiabetic agent ertugliflozin is described. The compd. belongs to a new class of SGLT2 inhibitors bearing a dioxa-bicyclo[3.2.1]octane motif. This article describes the crit. role that org. synthesis played in both influencing our medicinal chem. strategy and speeding up the progression of our program.
- 150(a) Miao, Z.; Nucci, G.; Amin, N.; Sharma, R.; Mascitti, V.; Tugnait, M.; Vaz, A. D.; Callegari, E.; Kalgutkar, A. S. Pharmacokinetics, metabolism, and excretion of the antidiabetic agent ertugliflozin (PF-04971729) in healthy male subjects. Drug Metab. Dispos. 2013, 41, 445– 456, DOI: 10.1124/dmd.112.049551[Crossref], [PubMed], [CAS], Google Scholar.150ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXitlGisb4%253D&md5=a6ad9f69b2d43b160cb2eec29bdd7c53Pharmacokinetics, metabolism, and excretion of the antidiabetic agent ertugliflozin (PF-04971729) in healthy male subjectsMiao, Zhuang; Nucci, Gianluca; Amin, Neeta; Sharma, Raman; Mascitti, Vincent; Tugnait, Meera; Vaz, Alfin D.; Callegari, Ernesto; Kalgutkar, Amit S.Drug Metabolism & Disposition (2013), 41 (2), 445-456CODEN: DMDSAI; ISSN:1521-009X. (American Society for Pharmacology and Experimental Therapeutics)The disposition of ertugliflozin (PF-04971729), an orally active selective inhibitor of the sodium-dependent glucose cotransporter 2, was studied after a single 25-mg oral dose of [14C]-ertugliflozin to healthy human subjects. Mass balance was achieved with approx. 91% of the administered dose recovered in urine and feces. The total administered radioactivity excreted in feces and urine was 40.9% and 50.2%, resp. The absorption of ertugliflozin in humans was rapid with a Tmax at ∼1.0 h. Of the total radioactivity excreted in feces and urine, unchanged ertugliflozin collectively accounted for ∼35.3% of the dose, suggestive of moderate metabolic elimination in humans. The principal biotransformation pathway involved glucuronidation of the glycoside hydroxyl groups to yield three regioisomeric metabolites, M4a, M4b, and M4c (∼39.3% of the dose in urine), of which M4c was the major regioisomer (∼31.7% of the dose). The structure of M4a and M4c were confirmed to be ertugliflozin -4-O-β- and -3-O-β-glucuronide, resp., via comparison of the HPLC retention time and mass spectra with authentic stds. A minor metabolic fate involved oxidn. by cytochrome P 450 to yield monohydroxylated metabolites M1 and M3 and des-Et ertugliflozin (M2), which accounted for ∼5.2% of the dose in excreta. In plasma, unchanged ertugliflozin and the corresponding 4-O-β- (M4a) and 3-O-β- (M4c) glucuronides were the principal components, which accounted for 49.9, 12.2, and 24.1% of the circulating radioactivity. Overall, these data suggest that ertugliflozin is well absorbed in humans, and eliminated largely via glucuronidation.(b) Raje, S.; Callegari, E.; Sahasrabudhe, V.; Vaz, A.; Shi, H.; Fluhler, E.; Woolf, E. J.; Schildknegt, K.; Matschke, K.; Alvey, C.; Zhou, S.; Papadopoulos, D.; Fountaine, R.; Saur, D.; Terra, S. G.; Stevens, L.; Gaunt, D.; Cutler, D. L. Novel application of the two-period microtracer approach to determine absolute oral bioavailability and fraction absorbed of ertugliflozin. Clin. Transl. Sci. 2018, 11, 405– 411, DOI: 10.1111/cts.12549[Crossref], [PubMed], [CAS], Google Scholar.150bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXht12mt73N&md5=cea34332e94c6042e6affbf32f1718a3Novel Application of the Two-Period Microtracer Approach to Determine Absolute Oral Bioavailability and Fraction Absorbed of ErtugliflozinRaje, Sangeeta; Callegari, Ernesto; Sahasrabudhe, Vaishali; Vaz, Alfin; Shi, Haihong; Fluhler, Eric; Woolf, Eric J.; Schildknegt, Klaas; Matschke, Kyle; Alvey, Christine; Zhou, Susan; Papadopoulos, Dimitris; Fountaine, Robert; Saur, Didier; Terra, Steven G.; Stevens, Lloyd; Gaunt, Daniel; Cutler, David L.Clinical and Translational Science (2018), 11 (4), 405-411CODEN: CTSLCA; ISSN:1752-8062. (Wiley-Blackwell)Ertugliflozin, a sodium glucose cotransporter-2 inhibitor, is approved in the United States for treatment of type 2 diabetes mellitus. A novel two-period study design with 14C microtracer dosing in each period was used to det. abs. oral bioavailability (F) and fraction absorbed (Fa) of ertugliflozin. Eight healthy adult men received 100-μg i.v. 14C-ertugliflozin (400 nCi) dose 1 h after a 15-mg oral unlabeled ertugliflozin dose (period 1), followed by 100μg 14C-ertugliflozin orally along with 15 mg oral unlabeled ertugliflozin (period 2). Unlabeled ertugliflozin plasma concns. were detd. using high-performance liq.-chromatog. tandem mass spectrometry (HPLC-MS/MS). 14C-ertugliflozin plasma concns. were detd. using HPLC-accelerator mass spectrometry (AMS) and 14C urine concns. were detd. using AMS. F ((area under the curve (AUC)p.o./14C-AUCi.v.)*(14C-Dosei.v./Dosep.o.)) and Fa ((14C_Total_Urinep.o./14C_Total_Urinei.v.)* (14C-Dosei.v./14C-Dosep.o.)) were estd. Ests. of F and Fa were 105% and 111%, resp. Oral absorption of ertugliflozin was complete under fasted conditions and F was ∼100%. Ertugliflozin was well tolerated.(c) Fediuk, D. J.; Nucci, G.; Dawra, V. K.; Cutler, D. L.; Amin, N. B.; Terra, S. G.; Boyd, R. A.; Krishna, R.; Sahasrabudhe, V. Overview of the clinical pharmacology of ertugliflozin, a novel sodium-glucose cotransporter 2 (SGLT2) inhibitor. Clin. Pharmacokinet. 2020, 59, 949– 965, DOI: 10.1007/s40262-020-00875-1[Crossref], [PubMed], [CAS], Google Scholar150chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXot1agtrg%253D&md5=49dd2f1558dd9115e94b3eba3e1c9081Overview of the Clinical Pharmacology of Ertugliflozin, a Novel Sodium-Glucose Cotransporter 2 (SGLT2) InhibitorFediuk, Daryl J.; Nucci, Gianluca; Dawra, Vikas Kumar; Cutler, David L.; Amin, Neeta B.; Terra, Steven G.; Boyd, Rebecca A.; Krishna, Rajesh; Sahasrabudhe, VaishaliClinical Pharmacokinetics (2020), 59 (8), 949-965CODEN: CPKNDH; ISSN:0312-5963. (Springer International Publishing AG)Abstr.: Ertugliflozin, a selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), is approved in the US, EU, and other regions for the treatment of adults with type 2 diabetes mellitus (T2DM). This review summarizes the ertugliflozin pharmacokinetic (PK) and pharmacodynamic data obtained during phase I clin. development, which supported the registration and labeling of this drug. The PK of ertugliflozin was similar in healthy subjects and patients with T2DM. Oral absorption was rapid, with time to peak plasma concns. (Tmax) occurring at 1 h (fasted) and 2 h (fed) postdose. The terminal phase half-life ranged from 11 to 18 h and steady-state concns. were achieved by 6 days after initiating once-daily dosing. Ertugliflozin exposure increased in a dose-proportional manner over the tested dose range of 0.5-300 mg. Ertugliflozin is categorized as a Biopharmaceutical Classification System Class I drug with an abs. bioavailability of ∼ 100% under fasted conditions. Administration of the ertugliflozin 15 mg com. tablet with food resulted in no meaningful effect on ertugliflozin area under the plasma concn.-time curve (AUC), but decreased peak concns. (Cmax) by 29%. The effect on Cmax is not clin. relevant and ertugliflozin can be administered without regard to food. Mild, moderate, and severe renal impairment were assocd. with a ≤ 70% increase in ertugliflozin exposure relative to subjects with normal renal function, and no dose adjustment in renal impairment patients is needed based on PK results. Consistent with the mechanism of action of SGLT2 inhibitors, 24-h urinary glucose excretion decreased with worsening renal function. In subjects with moderate hepatic impairment, a decrease in AUC (13%) relative to subjects with normal hepatic function was obsd. and not considered clin. relevant. Concomitant administration of metformin, sitagliptin, glimepiride, or simvastatin with ertugliflozin did not have clin. meaningful effects on the PK of ertugliflozin or the coadministered medications. Coadministration of rifampin decreased ertugliflozin AUC and Cmax by 39% and 15%, resp., and is not expected to affect efficacy in a clin. meaningful manner. This comprehensive evaluation supports administration to patients with T2DM without regard to prandial status and with no dose adjustments for coadministration with commonly prescribed drugs, or in patients with renal impairment or mild-to-moderate hepatic impairment based on ertugliflozin PK.
- 151Yan, Q.; Ding, N.; Li, Y. Synthesis and biological evaluation of novel dioxa-bicycle C-arylglucosides as SGLT2 inhibitors. Carbohydr. Res. 2016, 421, 1– 8, DOI: 10.1016/j.carres.2015.10.011[Crossref], [PubMed], [CAS], Google Scholar151https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXitVSqu73J&md5=6dcd4cadbc4d0e537c78b947faa4d9c4Synthesis and biological evaluation of novel dioxa-bicycle C-aryl glucosides as SGLT2 inhibitorsYan, Qi; Ding, Ning; Li, YingxiaCarbohydrate Research (2016), 421 (), 1-8CODEN: CRBRAT; ISSN:0008-6215. (Elsevier Ltd.)A series of novel C-aryl glucosides contg. dioxa-bicycle were synthesized and evaluated for inhibition activity against hSGLT2. Among the compds. tested, compd. I showed moderate SGLT2 inhibition activities at 700 nM. The results could benefit the discovery of new SGLT2 inhibitors.
- 152Rendell, M. S. Sotagliflozin: a combined SGLT1/SGLT2 inhibitor to treat diabetes. Expert Rev. Endocrinol. Metab. 2018, 13, 333– 339, DOI: 10.1080/17446651.2018.1537779[Crossref], [PubMed], [CAS], Google Scholar152https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitVyitb3L&md5=e3f23ce14df92eb05d7cf9e45214ed57Sotagliflozin: a combined SGLT1/SGLT2 inhibitor to treat diabetesRendell, Marc S.Expert Review of Endocrinology & Metabolism (2018), 13 (6), 333-339CODEN: EREMBI; ISSN:1744-6651. (Taylor & Francis Ltd.): Sotagliflozin is the first dual SGLT1/SGLT2 inhibitor developed for use in diabetes. The agent blocks SGLT2 in the kidneys and SGLT1 in the intestines resulting in reduced early phase glucose absorption and increased blood levels of GLP-1. Initial studies were directed at type 1 diabetes.: The published information on sotagliflozin is reviewed, along with the results of several pivotal Type 1 diabetes trials.: Sotagliflozin treatment lowers HbA1c and reduces glucose variability in Type 1 diabetes patients. Several other SGLT2 inhibitors have been assocd. with a tendency to diabetic ketoacidosis (DKA). In the type 1 trials, sotagliflozin treated individuals experienced DKA at a higher rate than placebo treated patients. An addnl. safety concern arises from the as yet unknown potential risks in women of child bearing potential. The sotagliflozin development program has now been extended to trials in type 2 diabetes. In type 2 diabetes, long-term studies will be needed to assess the benefits and risks of the agent as a possible alternative to currently marketed SGLT2 inhibitors.
- 153Li, Y.; Shi, Z.; Chen, L.; Zheng, S.; Li, S.; Xu, B.; Liu, Z.; Liu, J.; Deng, C.; Ye, F. Discovery of a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor (HSK0935) for the treatment of type 2 diabetes. J. Med. Chem. 2017, 60, 4173– 4184, DOI: 10.1021/acs.jmedchem.6b01818[ACS Full Text], [CAS], Google Scholar153https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXmslKktbY%253D&md5=7e35f9d80fd81c48a66934bde89098a0Discovery of a Potent, Selective Renal Sodium-Dependent Glucose Cotransporter 2 (SGLT2) Inhibitor (HSK0935) for the Treatment of Type 2 DiabetesLi, Yao; Shi, Zongjun; Chen, Lei; Zheng, Suxin; Li, Sheng; Xu, Bo; Liu, Zhenhong; Liu, Jianyu; Deng, Chongyang; Ye, FeiJournal of Medicinal Chemistry (2017), 60 (10), 4173-4184CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A new class of potent and highly selective SGLT2 inhibitors is disclosed. Compd. I (HSK0935) demonstrated excellent hSGLT2 inhibition of 1.3 nM and a high hSGLT1/hSGLT2 selectivity of 843-fold. It showed robust urinary glucose excretion in Sprague-Dawley (SD) rats and affected more urinary glucose excretion in Rhesus monkeys. Finally, an efficient synthetic route has been developed featuring a ring-closing cascade reaction to incorporate a double ketal 1-methoxy-6,8-dioxabicyclo[3.2.1]octane ring system.
- 154Wenzel, S. E.; Kamada, A. K. Zileuton: the first 5-lipoxygenase inhibitor for the treatment of asthma. Ann. Pharmacother. 1996, 30, 858– 864, DOI: 10.1177/106002809603000725[Crossref], [PubMed], [CAS], Google Scholar154https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XkvFSnsbw%253D&md5=8e354116ee2cefee87a2c0ff999a2022Zileuton: The first 5-lipoxygenase inhibitor for the treatment of asthmaWenzel, Sally E.; Kamada, Alan K.Annals of Pharmacotherapy (1996), 30 (7/8), 858-864CODEN: APHRER; ISSN:1060-0280. (Harvey Whitney Books Co.)A review with 34 refs. Zileuton, an orally active 5-lipoxygenase inhibitor that represents the first of a new class of medications to be used in the treatment of asthma is described. Zileuton has the ability to attenuate induced bronchospasm, produce some degree of bronchodilation, and provide antiinflammatory or steroid-sparing effects with both single doses (800 mg) and chronic treatment (400 and 600 mg). Zileuton has been studied in patients requiring daily inhaled β-adrenergic agonist treatment; however, data from pediatric populations and comparisons with other asthma medications are limited at this time. Adverse effects include dyspepsia and elevated liver enzymes (incidence ∼ 3%). One case of jaundice has been reported among the more than 5000 patients treated with zileuton. There is also some concern for drug interactions with hepatically cleared medications, such as theophylline.
- 155(a) Delorme, D.; Ducharme, Y.; Brideau, C.; Chan, C. C.; Chauret, N.; Desmarais, S.; Dubé, D.; Falgueyret, J. P.; Fortin, R.; Guay, J.; Hamel, P.; Jones, T. R.; Lépine, C.; Li, C.; McAuliffe, M.; McFarlane, C. S.; Nicoll-Griffith, D. A.; Riendeau, D.; Yergey, J. A.; Girard, Y. Dioxabicyclooctanyl naphthalenenitriles as nonredox 5-lipoxygenase inhibitors: structure-activity relationship study directed toward the improvement of metabolic stability. J. Med. Chem. 1996, 39, 3951– 3970, DOI: 10.1021/jm960301c[ACS Full Text.], [CAS], Google Scholar155ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XlsVekurg%253D&md5=4f1629295def29b1d4115c5cee59036bDioxabicyclooctanyl Naphthalenenitriles as Nonredox 5-Lipoxygenase Inhibitors: Structure-Activity Relationship Study Directed toward the Improvement of Metabolic StabilityDelorme, Daniel; Ducharme, Yves; Brideau, Christine; Chan, Chi-Chung; Chauret, Nathalie; Desmarais, Sylvie; Dube, Daniel; Falgueyret, Jean-Pierre; Fortin, Rejean; et al.Journal of Medicinal Chemistry (1996), 39 (20), 3951-3970CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Naphthalenic lignan lactone I (L-702,539), a potent and selective 5-lipoxygenase (5-LO) inhibitor, is extensively metabolized at two different sites: the tetrahydropyran and the lactone rings. Early knowledge of the metabolic pathways triggered and directed a structure-activity relationship study aimed toward the improvement of metabolic stability in this series. The best modifications discovered, i.e., replacement of the lactone ring by a nitrile group, replacement of the tetrahydropyran ring by a 6,8-dioxabicyclo[3.2.1]octanyl moiety, and replacement of the pendant Ph ring by a 3-furyl ring, were incorporated in a single mol. to produce inhibitor II (L-708,780). II inhibits the oxidn. of arachidonic acid to 5-hydroperoxyeicosatetraenoic acid by 5-LO (IC50 = 190 nM) and the formation of leukotriene B4 in human polymorphonuclear leukocytes (IC50 = 3 nM) as well as in human whole blood (IC50 = 150 nM). The good inhibitory profile shown by naphthalenenitrile II is accompanied by an improved resistance to oxidative metab. In addn., II is orally active in the functional model of antigen-induced bronchoconstriction in allergic squirrel monkeys (95% inhibition at 0.1 mg/kg).(b) Hamel, P.; Riendeau, D.; Brideau, C.; Chan, C.-C.; Desmarais, S.; Delorme, D.; Dube, D.; Ducharme, Y.; Ethier, D.; Grimm, E.; Falgueyret, J.-P.; Guay, J.; Jones, T. R.; Kwong, E.; McFarlane, C. S.; Piechuta, H.; Roumi, M.; Tagari, P.; Young, R. N.; Girard, Y. Substituted (pyridylmethoxy)naphthalenes as potent and orally active 5-lipoxygenase inhibitor. synthesis, biological profile, and pharmacokinetics of L-739,010. J. Med. Chem. 1997, 40, 2866– 2875, DOI: 10.1021/jm970046b[ACS Full Text], [CAS], Google Scholar155bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXlt1Kks7k%253D&md5=2f8e56dac331ebc7293780cc49941971Substituted (Pyridylmethoxy)naphthalenes as Potent and Orally Active 5-Lipoxygenase Inhibitors: Synthesis, Biological Profile, and Pharmacokinetics of L-739,010Hamel, Pierre; Riendeau, Denis; Brideau, Christine; Chan, Chi-Chung; Desmarais, Sylvie; Delorme, Daniel; Dube, Daniel; Ducharme, Yves; Ethier, Diane; Grimm, Erich; Falgueyret, Jean-Pierre; Guay, Jocelyne; Jones, Tom R.; Kwong, Elizabeth; McAuliffe, Malia; McFarlane, Cyril S.; Piechuta, Hanna; Roumi, Marie; Tagari, Philip; Young, Robert N.; Girard, YvesJournal of Medicinal Chemistry (1997), 40 (18), 2866-2875CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Dioxabicyclooctanyl naphthalenenitriles have been reported as a class of potent and nonredox 5-lipoxygenase (5-LO) inhibitors. These bicyclo derivs. were shown to be metabolically more stable than their tetrahydropyranyl counterparts but were not well orally absorbed. Replacement of the Ph ring in the naphthalenenitrile L 708,780 by a pyridine ring leads to the potent and orally absorbed inhibitor 3g (L-739,010, 2-cyano-4-(3-furyl)-7-[[6-[3-(3-hydroxy-6,8-dioxabicyclo[3.2.1]octanyl)]-2-pyridyl]methoxy]naphthalene). Compd. 3g inhibits 5-HPETE prodn. by human 5-LO and LTB4 biosynthesis by human PMN leukocytes and human whole blood (IC50s of 20, 1.6, and 42 nM, resp.). Deriv. 3g is orally active in the rat pleurisy model (inhibition of LTB4, ED50 = 0.3 mg/kg) and in the anesthetized dog model (inhibition of ex vivo whole blood LTB4 and urinary LTE4, ED50 = 0.45 and 0.23 μg/kg/min, resp., i.v. infusion). In addn., 3g shows excellent functional activity against ovalbumin-induced dyspnea in rats (60% inhibition at 0.5 mg/kg, 4 h pretreatment) and Ascaris-induced bronchoconstriction in conscious sheep (50% and >85% inhibition in early and late phases, resp. at 2.5 μg/kg/min, i.v. infusion) and, more particularly in the conscious antigen sensitive squirrel monkey model (53% inhibition of the increase in RL and 76% in the decrease of Cdyn, at 0.1 mg/kg, po). In rats and dogs, 3g presents excellent pharmacokinetics (estd. half-lives of 5 and 16 h, resp.) and bioavailabilities (26% and 73% when dosed as its hydrochloride salt at doses of 20 and 10 mg/kg, resp., in methocel suspension). Based on its overall biol. profile, compd. 3g has been selected for preclin. animal toxicity studies.
- 156(a) Chauret, N.; Nicoll-Griffith, D.; Friesen, R.; Li, C.; Trimble, L.; Dubé, D.; Fortin, R.; Girard, Y.; Yergey, J. Microsomal metabolism of the 5-lipoxygenase inhibitors L-746,530 and L-739,010 to reactive intermediates that covalently bind to protein: the role of the 6,8-dioxabicyclo[3.2.1]octanyl moiety. Drug Metab. Dispos. 1995, 23, 1325– 1334[PubMed], [CAS], Google Scholar.156ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XhvF2gtQ%253D%253D&md5=01f2cd69374a1f921559e5ab49b48fbbMicrosomal metabolism of the 5-lipoxygenase inhibitors L-746,530 and L-739,010 to reactive intermediates that covalently bind to protein: the role of the 6,8-dioxabicyclo[3.2.1]octanyl moietyChauret, N.; Nicoll-Griffith, D.; Friesen, R.; Li, C.; Trimble, L.; Dube, D.; Fortin, R.; Girard, Y.; Yergey, J.Drug Metabolism and Disposition (1995), 23 (12), 1325-34CODEN: DMDSAI; ISSN:0090-9556. (Williams & Wilkins)Hepatic microsomes from different species were used to study the oxidative metab. of L-746,530 and L-739,010, two potent and specific 5-lipoxygenase inhibitors. HPLC anal. of the incubates obtained from the microsomal incubations of L-739,010 and L-746,530 showed only traces of metabolites. However, recovery of the starting material in the supernatant was less than quant. in all of the species studied (∼90% in rat.vtheta. ∼70% in the dexamethasone-induced rat, ∼70-90% in humans, and ∼60% in the rhesus monkey for both compds.). The recovery of the starting material was found to be time- and NADPH-dependent, suggesting that metabolite(s) were formed and reacting with the microsomal proteins. Evidence that the cytochrome P 4503A (CYP3A) contributed to the formation of the reactive metabolite(s) was shown by the low recovery of material that was obsd. upon incubation with microsomes obtained from dexamethasone-treated rats (a CYP3A inducer), compared with microsomes obtained from untreated rats. Also, the recovery of material was improved when troleandomycin, a CYP3A inhibitor, was added to rhesus monkey microsomal incubations (25% more parent compds. detected in the supernatant with 100 μM of troleandomycin). Using radiolabeled L-746,530 and gel electrophoresis anal., it was confirmed that radiolabeled material was covalently bound to the microsomal protein. Incubations of L-739,010 and L-746,530 in the presence of semicarbazide resulted, in both cased, in the formation of two adducts. Using a combination of NMR, liq. second-ion MS, and UV techniques, these adducts were identified as isomers of an oxidized metabolite that had been trapped by semicarbazide. The site of oxidn. was detd. to be on the dioxabicyclo moiety. The importance of this moiety in the formation of reactive metabolite(s) was verified by incubating analogs of the 5-lipoxygenase inhibitors that contained blocking Me groups at the proposed site of oxidn. on the bicyclo moiety. Incubations of these gemdimethyl analogs of L-746,530 and L-739,010 with microsomes from different species resulted in significantly improved recovery of the starting material (∼94% in the rat, 85% in the dexamethasone-induced rat, 95% in humans, and 85% in the rhesus monkey for both compds.) and significantly less radioactive binding to the microsomal protein.(b) Zhang, K. E.; Naue, J. A.; Arison, B.; Vyas, K. P. Microsomal metabolism of the 5-lipoxygenase inhibitor L-739,010: evidence for furan bioactivation. Chem. Res. Toxicol. 1996, 9, 547– 554, DOI: 10.1021/tx950183g[ACS Full Text], [CAS], Google Scholar156bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28Xpt1agsw%253D%253D&md5=3f25fc32090372817fd7d247c2dc2910Microsomal Metabolism of the 5-Lipoxygenase Inhibitor L-739,010: Evidence for Furan BioactivationZhang, Kanyin E.; Naue, Jeanne A.; Arison, Byron; Vyas, Kamlesh P.Chemical Research in Toxicology (1996), 9 (2), 547-54CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)The novel 5-lipoxygenase inhibitor 3-cyano-1-(3-furyl)-6-{[6-(3α-hydroxy-6,8-dioxabicyclo[3.2.1]octanyl)pyridin-2-yl]methoxyl}naphthalene (L-739,010), when administered to rats and rhesus monkeys, was found to produce metabolites which appeared to be covalently bound to plasma proteins. Incubation of [14C]L-739,010 with rat liver microsomes did not yield appreciable amts. of sol. metabolites but resulted in covalent binding to microsomal proteins. The covalent binding was NADPH-dependent and was enhanced by 1.5- and 2-fold when rats were pretreated with phenobarbital and dexamethasone, resp. Addn. of triacetyloleandomycin and diethyldithiocarbamate to the incubation mixt. inhibited the covalent binding by 60% and 46%, resp. These findings suggest that the cytochrome P 450 3A family of enzymes play an important role in the bioactivation of L-739,010. The presence of GSH attenuated the covalent binding by 50%, while methoxylamine, an aldehyde trapping agent, blocked the covalent binding completely and, concurrently, produced several sol. metabolic adducts. Subsequently, major methoxylamine adducts were identified by LC-MS/MS and NMR as O-methyloximes of the ring-opened furan moiety of L-739,010. Incubation of L-739,010 with methoxylamine and hepatic microsomes from dog, rhesus monkey, and human produced similar metabolic adducts as those formed by rat liver microsomes. Therefore, under these exptl. conditions, the furan moiety, which undergoes oxidative cleavage to the highly reactive 2-butene-1,4-dialdehyde, represents the major site of L-739,010 biotransformation. This putative reactive intermediate could react with microsomal proteins in vitro and physiol. proteins in vivo. Since furan bioactivation is believed to be responsible for the toxicity of many furan-contg. compds., the furan moiety of L-739,010 may be regarded as undesirable.
- 157Ohtake, Y.; Sato, T.; Kobayashi, T.; Nishimoto, M.; Taka, N.; Takano, K.; Yamamoto, K.; Ohmori, M.; Yamaguchi, M.; Takami, K.; Yeu, S.; Ahn, K.; Matsuoka, H.; Morikawa, K.; Suzuki, M.; Hagita, H.; Ozawa, K.; Yamaguchi, K.; Kato, M.; Ikeda, S. Discovery of tofogliflozin, a novel C-arylglucoside with an O-spiroketal ring system, as a highly selective sodium glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes. J. Med. Chem. 2012, 55, 7828– 7840, DOI: 10.1021/jm300884k[ACS Full Text], [CAS], Google Scholar157https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtFOrurfN&md5=174a0538c13a286dd320a52395e1dd85Discovery of Tofogliflozin, a Novel C-Arylglucoside with an O-Spiroketal Ring System, as a Highly Selective Sodium Glucose Cotransporter 2 (SGLT2) Inhibitor for the Treatment of Type 2 DiabetesOhtake, Yoshihito; Sato, Tsutomu; Kobayashi, Takamitsu; Nishimoto, Masahiro; Taka, Naoki; Takano, Koji; Yamamoto, Keisuke; Ohmori, Masayuki; Yamaguchi, Marina; Takami, Kyoko; Yeu, Sang-Yong; Ahn, Koo-Hyeon; Matsuoka, Hiroharu; Morikawa, Kazumi; Suzuki, Masayuki; Hagita, Hitoshi; Ozawa, Kazuharu; Yamaguchi, Koji; Kato, Motohiro; Ikeda, SachiyaJournal of Medicinal Chemistry (2012), 55 (17), 7828-7840CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Inhibition of sodium glucose cotransporter 2 (SGLT2) has been proposed as a novel therapeutic approach to treat type 2 diabetes. In our efforts to discover novel inhibitors of SGLT2, we first generated a 3D pharmacophore model based on the superposition of known inhibitors. A search of the Cambridge Structural Database using a series of pharmacophore queries led to the discovery of an O-spiroketal C-arylglucoside scaffold. Subsequent chem. examn. combined with computational modeling resulted in the identification of the clin. candidate CSG452 (tofogliflozin), which is currently under phase III clin. trials.
- 158(a) Lv, B.; Xu, B.; Feng, Y.; Peng, K.; Xu, G.; Du, J.; Zhang, L.; Zhang, W.; Zhang, T.; Zhu, L.; Ding, H.; Sheng, Z.; Welihinda, A.; Seed, B.; Chen, Y. Exploration of O-spiroketal C-arylglucosides as novel and selective renal sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors. Bioorg. Med. Chem. Lett. 2009, 19, 6877– 6881, DOI: 10.1016/j.bmcl.2009.10.088[Crossref], [PubMed], [CAS], Google Scholar.158ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsVWht7vJ&md5=9b7461b86601f207bd56759152b5ae4cExploration of O-spiroketal C-aryl-glucosides as novel and selective renal sodium-dependent glucose co-transporter 2 (SGLT2) inhibitorsLv, Binhua; Xu, Baihua; Feng, Yan; Peng, Kun; Xu, Ge; Du, Jiyan; Zhang, Lili; Zhang, Wenbin; Zhang, Ting; Zhu, Liangcheng; Ding, Haifeng; Sheng, Zelin; Welihinda, Ajith; Seed, Brian; Chen, YuanweiBioorganic & Medicinal Chemistry Letters (2009), 19 (24), 6877-6881CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A series of novel O-spiroketal C-aryl-glucosides, e.g. I, have been prepd. and evaluated in cell-based functional assays for activity against human sodium-dependent glucose co-transporters 1 and 2 (SGLT1 and SGLT2). The core spiro[iso-benzofuran-1,2'-pyran] structure proved to be an effective scaffold for diversification and a no. of compds. with single digit nano-molar potency and high selectivity have been synthesized. Compd. I promoted glucosuria when administered in vivo in rats and produced a significant blood glucose redn. effect.(b) Kasahara-Ito, N.; Fukase, H.; Ogama, Y.; Saito, T.; Ohba, Y.; Shimada, S.; Takano, Y.; Ichihara, T.; Terao, K.; Nakamichi, N.; Kumagai, Y.; Ikeda, S. Pharmacokinetics and pharmacodynamics of tofogliflozin (a selective SGLT2 inhibitor) in healthy male subjects. Drug Res. 2017, 67, 349– 357, DOI: 10.1055/s-0043-104779[Crossref], [CAS], Google Scholar158bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXmtlOqur8%253D&md5=6dde4f95f62682a817b5aa9e5268dacdPharmacokinetics and Pharmacodynamics of Tofogliflozin (a Selective SGLT2 Inhibitor) in Healthy Male SubjectsKasahara-Ito, Nahoko; Fukase, Hiroyuki; Ogama, Yoichiro; Saito, Tomohisa; Ohba, Yasuhiro; Shimada, Sumire; Takano, Yasuki; Ichihara, Tomoko; Terao, Kimio; Nakamichi, Noboru; Kumagai, Yuji; Ikeda, SachiyaDrug Research (Stuttgart, Germany) (2017), 67 (6), 349-357CODEN: DRSGAO; ISSN:2194-9379. (Georg Thieme Verlag)Purpose: Tofogliflozin is a selective oral inhibitor of sodium-glucose co-transporter 2 for treatment of type 2 diabetes mellitus. The pharmacokinetics, pharmacodynamics, and safety of tofogliflozin were investigated in healthy male subjects. Methods: Three studies were conducted: single-ascending dose study (10-640 mg) in 56 Japanese and 24 Caucasian subjects; multiple-ascending dose study (2.5-80 mg once daily for 7 days) in 24 Japanese subjects; and food-effect study (20-40 mg) in 30 Japanese subjects. Results: Tofogliflozin was absorbed rapidly and eliminated from the systemic circulation with a t1/2 of 5-6 h. Exposure increased dose-proportionally up to 320 mg. Body wt.-cor. exposure was similar between Japanese and Caucasian subjects. Urinary excretion of tofogliflozin ranged from 17.1 to 27.4% of dose. Tofogliflozin did not accumulate with once daily administration. Food intake decreased Cmax by approx. 30% but did not change AUC0-inf. Tofogliflozin caused dose-dependent daily urinary glucose excretion (UGE0-24h), but food intake condition at administration did not affect it. The exposure-response relationship between plasma av. concn. of tofogliflozin (Cavg) and UGE0-24h fitted Emax model well. There were no serious adverse events leading to discontinuation or episodes of hypoglycemia. Conclusions: Single and multiple administration of tofogliflozin were generally well tolerated. Exposure to tofogliflozin was dose-proportional up to 320 mg and did not accumulate with multiple once-a-day administration. The model suggests more than 100 ng/mL Cavg corresponding to the dose of between 20 and 40 mg leads to almost max. effect of tofogliflozin.
- 159(a) Seward, E. M.; Carlson, E.; Harrison, T.; Haworth, K. E.; Herbert, R.; Kelleher, F. J.; Kurtz, M. M.; Moseley, J.; Owen, S. N.; Owens, A. P.; Sadowski, S. J.; Swain, C. J.; Williams, B. J. Spirocyclic NK1 antagonists I: [4.5] and [5.5]-spiroketals. Bioorg. Med. Chem. Lett. 2002, 12, 2515– 2518, DOI: 10.1016/S0960-894X(02)00506-1[Crossref], [PubMed], [CAS], Google Scholar.159ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XmsVWju74%253D&md5=cb0865b5cb065e3c39b875f0a290b9deSpirocyclic NK1 antagonists I: [4.5] and [5.5]-SpiroketalsSeward, Eileen M.; Carlson, Emma; Harrison, Timothy; Haworth, Karen E.; Herbert, Richard; Kelleher, Fintan J.; Kurtz, Marc M.; Moseley, Jonathan; Owen, Simon N.; Owens, Andrew P.; Sadowski, Sharon J.; Swain, Christopher J.; Williams, Brian J.Bioorganic & Medicinal Chemistry Letters (2002), 12 (18), 2515-2518CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)A series of novel spiroketal-based NK1 antagonists is described. The effect of modifications to the spiroether ring and arom. substituents are discussed, leading to the identification of compds. with high affinity and excellent CNS penetration.(b) Quach, R.; Furkert, D. P.; Brimble, M. A. Gold Catalysis: Synthesis of Spiro, Bridged, and Fused Ketal Natural Products. Org. Biomol. Chem. 2017, 15, 3098– 3104, DOI: 10.1039/C7OB00496F[Crossref], [PubMed], [CAS], Google Scholar.159bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXktVSgsro%253D&md5=7a55273502ceac5b0e77e680043750b9Gold catalysis: synthesis of spiro, bridged, and fused ketal natural productsQuach, Rachelle; Furkert, Daniel P.; Brimble, Margaret A.Organic & Biomolecular Chemistry (2017), 15 (15), 3098-3104CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)A review. In the last decade the use of homogeneous gold catalysts has rapidly grown and become a valuable tool for complex natural product synthesis. Spiroketal natural products are valuable targets for total synthesis and medicinal chem. applications. The use of gold catalysts has emerged as a useful tool to synthesize these privileged scaffolds. This review summarizes the application of gold catalysis for the syntheses of spiro, bridged and fused ketal natural products.(c) Choi, K. W.; Brimble, M. A. Synthesis of spiroacetal-nucleosides as privileged natural product-like scaffolds. Org. Biomol. Chem. 2009, 7, 1424– 36, DOI: 10.1039/b818314g[Crossref], [PubMed], [CAS], Google Scholar.159chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXjtlOiurs%253D&md5=7acf90ce72ff7047bb66cad9f363f9b0Synthesis of spiroacetal-nucleosides as privileged natural product-like scaffoldsChoi, Ka Wai; Brimble, Margaret A.Organic & Biomolecular Chemistry (2009), 7 (7), 1424-1436CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)The elaboration of a 6,6-spiroacetal scaffold to incorporate a nucleoside unit at the anomeric position is described. The novel spiroacetal-nucleoside hybrids, e.g. I, were generated via nucleosidation of acetoxy-spiroacetal with a series of silylated nucleobases under Vorbrueggen conditions.(d) Zhang, F. M.; Zhang, S. Y.; Tu, Y. Q. Recent progress in the isolation, bioactivity, biosynthesis, and total synthesis of natural spiroketals. Nat. Prod. Rep. 2018, 35, 75– 104, DOI: 10.1039/C7NP00043J[Crossref], [PubMed], [CAS], Google Scholar.159dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtlOktLc%253D&md5=9103edde941b264841c85c5f5ee2bdc7Recent progress in the isolation, bioactivity, biosynthesis, and total synthesis of natural spiroketalsZhang, Fu-Min; Zhang, Shu-Yu; Tu, Yong-QiangNatural Product Reports (2018), 35 (1), 75-104CODEN: NPRRDF; ISSN:0265-0568. (Royal Society of Chemistry)A review on. Spiroketal (spiroacetal), a common moiety in numerous natural products, drugs and functional mols., has been a central topic in org. chem. for a long time. Owing to their structural diversity, important bioactivity and functional irreplaceability, natural spiroketals have attracted the interest of natural product chemists, medical chemists, biol. chemists, agricultural chemists, synthetic chemists, and chem. biologists. In this review, we focus on the overview of the isolation, bioactivity, biosynthesis and total synthesis of spiroketals from 2011 to July 2017.(e) Lenci, E. Synthesis and biological properties of spiroacetal-containing small molecules. Small Molecule Drug Discovery 2020, 225– 245, DOI: 10.1016/B978-0-12-818349-6.00008-X
- 160(a) Ghosh, A. K.; Dawson, Z. L.; Mitsuya, H. Darunavir, a conceptually new HIV-1 protease inhibitor for the treatment of drug-resistant HIV. Bioorg. Med. Chem. 2007, 15, 7576– 7580, DOI: 10.1016/j.bmc.2007.09.010[Crossref], [PubMed], [CAS], Google Scholar.160ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtF2msL%252FJ&md5=56aa3f9486e422657e4da60cd6f0c526Darunavir, a conceptually new HIV-1 protease inhibitor for the treatment of drug-resistant HIVGhosh, Arun K.; Dawson, Zachary L.; Mitsuya, HiroakiBioorganic & Medicinal Chemistry (2007), 15 (24), 7576-7580CODEN: BMECEP; ISSN:0968-0896. (Elsevier Ltd.)Our structure-based design strategies which specifically target the HIV-1 protease backbone, resulted in a no. of exceedingly potent nonpeptidyl inhibitors. One of these inhibitors, darunavir (TMC114), contains a privileged, structure-based designed high-affinity P2 ligand, 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane (bis-THF). Darunavir has recently been approved for the treatment of HIV/AIDS patients harboring multidrug-resistant HIV-1 variants that do not respond to previously existing HAART regimens.(b) Ghosh, A. K.; Sridhar, P. R.; Kumaragurubaran, N.; Koh, Y.; Weber, I. T.; Mitsuya, H. Bis-tetrahydrofuran: a privileged ligand for darunavir and a new generation of HIV protease inhibitors that combat drug resistance. ChemMedChem 2006, 1, 939– 950, DOI: 10.1002/cmdc.200600103[Crossref], [PubMed], [CAS], Google Scholar.160bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXjsVCmu7w%253D&md5=e9826330e807476b916d69e86ff55a40Bis-tetrahydrofuran: a privileged ligand for darunavir and a new generation of HIV protease inhibitors that combat drug resistanceGhosh, Arun K.; Sridhar, Perali Ramu; Kumaragurubaran, Nagaswamy; Koh, Yasuhiro; Weber, Irene T.; Mitsuya, HiroakiChemMedChem (2006), 1 (9), 939-950CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. The structure-based design of bis-tetrahydrofuranyl urethane has emerged as a privileged nonpeptide P2 ligand for a variety of highly potent HIV-1 protease inhibitors. Incorporation of this ligand provided HIV protease inhibitors with exceedingly potent antiviral activity and superior activity against multi-PI-resistant variants relative to other FDA-approved PIs. Recently, TMC-114 (darunavir) was approved by the FDA for treatment of drug-resistant HIV. GW640385 (brecanavir), which incorporates bis-THF as the P2 ligand, is currently in Phase-III clin. development. The bis-THF ligand was specifically designed to fill in the hydrophobic S2 pocket effectively and to promote extensive hydrogen bonding with the protein backbone in the enzyme S2 site. The protein-ligand x-ray crystal structures with TMC-114 and other inhibitors with the bis-THF ligand revealed extensive interactions with the backbone of residues Asp29 and Asp30 at the S2 site. The current design concept targeting the protein backbone may serve as an important guide to combat drug resistance. Further design and synthesis of conceptually novel inhibitors are in progress.(c) Ghosh, A. K. Harnessing nature’s Insight: design of aspartyl protease inhibitors from treatment of drug-resistant HIV to Alzheimer’s disease. J. Med. Chem. 2009, 52, 2163– 2176, DOI: 10.1021/jm900064c[ACS Full Text], [CAS], Google Scholar160chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXktVSlsb0%253D&md5=27bc9377ab9cefffb9c009cc08a6faabHarnessing Nature's Insight: Design of Aspartyl Protease Inhibitors from Treatment of Drug-Resistant HIV to Alzheimer's DiseaseGhosh, Arun K.Journal of Medicinal Chemistry (2009), 52 (8), 2163-2176CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review discussing development of drugs based on synthesis of compds. related to naturally occurring mols. A research program was initiated in 1994 aimed at synthesizing bioactive natural products with interesting structural features. This endeavor resulted in the total synthesis of numerous targets, covering over two dozen or so different structural families. Some notable examples of accomplished bioactive targets include novel and exceedingly potent microtubule stabilizing agents laulimalide and peloruside A; a potent microtubule destabilizing agent cryptophycin 52; anticancer agents amphidinolide T, amphidinolide W, and lasonolide A; antibiotic agent madumycin II; pancreatic lipase inhibitor tetrahydrolipstatin; novel actin inhibitory agents doliculide and jasplakinolide; novel antibacterial agent platensimycin; and a histone deacetylase inhibitor largazole. The unique structural features of these natural products required the development of new synthetic tools and methodologies for their synthesis. In the context of our synthesis of various bioactive targets, a variety of new and practical asym. reactions were developed based on intermol. and intramol. metal chelation. Notable carbon-carbon bond forming synthetic methodologies include highly diastereoselective syn- and anti-aldol reactions, asym. inter- and intramol. Diels-Alder and hetero Diels-Alder reactions, and asym. multicomponent reactions. The scope and utility of these methodologies have been demonstrated through the synthesis of a variety of bioactive mols. Another important objective of our synthetic endeavors is to carry out detailed biol. studies and explore the medicinal potential of these target mols. This crossover, to focus on the biol. aspects of these natural products has led to a no. of unexpected but very significant results.
- 161Vermeir, M.; Lachau-Durand, S.; Mannens, G.; Cuyckens, F.; van Hoof, B.; Raoof, A. Absorption, metabolism, and excretion of darunavir, a new protease inhibitor, administered alone and with low-dose ritonavir in healthy subjects. Drug Metab. Dispos. 2009, 37, 809– 820, DOI: 10.1124/dmd.108.024109[Crossref], [PubMed], [CAS], Google Scholar161https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXktVSku7Y%253D&md5=a7a4d7e5531622b8cfc20a3be8b1d061Absorption, metabolism, and excretion of darunavir, a new protease inhibitor, administered alone and with low-dose ritonavir in healthy subjectsVermeir, Marc; Lachau-Durand, Sophie; Mannens, Geert; Cuyckens, Filip; van Hoof, Bart; Raoof, ArazDrug Metabolism and Disposition (2009), 37 (4), 809-820CODEN: DMDSAI; ISSN:0090-9556. (American Society for Pharmacology and Experimental Therapeutics)Absorption, metab., and excretion of darunavir, an inhibitor of human immunodeficiency virus protease, was studied in eight healthy male subjects after a single oral dose of 400 mg of [14C]-darunavir given alone (unboosted subjects) or with ritonavir [100 mg b.i.d. 2 days before and 7 days after darunavir administration (boosted subjects)]. Plasma exposure to darunavir was 11-fold higher in boosted subjects. Total recoveries of radioactivity in urine and feces were 93.9 and 93.5% of administered radioactivity in unboosted and boosted subjects, resp. The most radio-activity was recovered in feces (81.7% in unboosted subjects and 79.5% in boosted subjects, compared with 12.2 and 13.9% recovered in urine, resp.). Darunavir was extensively metabolized in unboosted subjects, mainly by carbamate hydrolysis, iso-Bu aliph. hydroxylation, and aniline arom. hydroxylation and to a lesser extent by benzylic arom. hydroxylation and glucuronidation. Total excretion of unchanged darunavir accounted for 8.0% of the dose in unboosted subjects. Boosting with ritonavir resulted in significant inhibition of carbamate hydrolysis, iso-Bu aliph. hydroxylation, and aniline arom. hydroxylation but had no effect on arom. hydroxylation at the benzylic moiety, whereas excretion of glucuronide metabolites was markedly increased but still represented a minor pathway. Total excretion of unchanged darunavir accounted for 48.8% of the administered dose in boosted subjects as a result of the inhibition of darunavir metab. by ritonavir. Unchanged darunavir in urine accounted for 1.2% of the administered dose in unboosted subjects and 7.7% in boosted subjects, indicating a low renal clearance. Darunavir administered alone or with ritonavir was well tolerated.
- 162Sadler, B. M.; Chittick, G. E.; Polk, R. E.; Slain, D.; Kerkering, T. M.; Studenberg, S. D.; Lou, Y.; Moore, K. H.; Woolley, J.; Stein, D. S. Metabolic disposition and pharmacokinetics of [14C]-amprenavir, a human immunodeficiency virus type 1 (HIV-1) protease inhibitor, administered as a single oral dose to healthy male subjects. J. Clin. Pharmacol. 2001, 41, 386– 396, DOI: 10.1177/00912700122010249[Crossref], [PubMed], [CAS], Google Scholar162https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXivVGkt78%253D&md5=93d9ef0b96949959c2d85f7427c58951Metabolic disposition and pharmacokinetics of [14C]-amprenavir, a human immunodeficiency virus type 1 (HIV-1) protease inhibitor, administered as a single oral dose to healthy male subjectsSadler, Brian M.; Chittick, Gregory E.; Polk, Ronald E.; Slain, Douglas; Kerkering, Thomas M.; Studenberg, Scott D.; Lou, Yu; Moore, Katy H. P.; Woolley, Joseph L.; Stein, Daniel S.Journal of Clinical Pharmacology (2001), 41 (4), 386-396CODEN: JCPCBR; ISSN:0091-2700. (Sage Publications)The objective of this study was to det. the metabolic profile, routes of elimination, and total recovery of amprenavir and its metabolites after a single oral dose of [14C]-amprenavir. Six healthy male subjects each received a single oral 630 mg dose of amprenavir contg. 95.76 μCi of [14C]-amprenavir in this Phase I mass balance study. The metabolic disposition of amprenavir was detd. through analyses of radiocarbon in whole blood, plasma, urine, and stool samples, collected for a period of 10 to 17 days postdosing. Cerebral spinal fluid (CSF) sampling was conducted on day 1. The ratio of unchanged amprenavir AUC0→∞ to plasma radiocarbon was 27%, suggesting that most of the radiocarbon was metabolites. The median total recovery of the administered dose of radiocarbon was 89% (range: 66%-93%), with 75% (range: 56%-80%) recovered in the feces and 14% (range: 10%-17%) in the urine. Most of the recovered radiocarbon in the feces and urine was excreted within 240 and 48 h postdose, resp. Of the 75% of the radiocarbon dose recovered in the feces, 62% was identified as a metabolite resulting from dioxidn. of the THF ring (GW549445X) and 32% as a metabolite resulting from subsequent oxidn. of the p-aniline sulfonate group (GW549444X). Unchanged amprenavir was below the limit of quantitation in feces and urine. Therefore, approx. 94% of the dose excreted in the feces was accounted for by these two metabolites. Concns. of radiocarbon in the CSF were below the limit of quantitation in 5 of 6 subjects sampled. In summary, oral amprenavir is extensively metabolized in humans, with concns. of unchanged drug below the limits of quantitation in urine and feces. The majority (75%) of administered radiocarbon was excreted in feces.
- 163(a) Ghosh, A. K.; Xu, C.; Rao, K. V.; Baldridge, A.; Agniswamy, J.; Wang, Y.; Weber, I. T.; Aoki, M.; Miguel, S.; Amano, M.; Mitsuya, H. Probing multidrug-resistance and protein-ligand interactions with oxatricyclic designed ligands in HIV-1 protease inhibitors. ChemMedChem 2010, 5, 1850– 1854, DOI: 10.1002/cmdc.201000318[Crossref], [PubMed], [CAS], Google Scholar.163ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtlClu7vM&md5=6f5b753c82f353959b720ecfc550136dProbing Multidrug-Resistance and Protein-Ligand Interactions with Oxatricyclic Designed Ligands in HIV-1 Protease InhibitorsGhosh, Arun K.; Xu, Chun-Xiao; Rao, Kalapala Venkateswara; Baldridge, Abigail; Agniswamy, Johnson; Wang, Yuan-Fang; Weber, Irene T.; Aoki, Manabu; Miguel, Salcedo Gomez Pedro; Amano, Masayuki; Mitsuya, HiroakiChemMedChem (2010), 5 (11), 1850-1854CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)Design and synthesis of HIV-1 protease inhibitor GRL-0519A and its crystal structure with HIV1 protease is investigated.(b) Zhang, H.; Wang, Y.; Shen, C.; Agniswamy, J.; Rao, K. V.; Xu, C.; Ghosh, A. K.; Harrison, R. W.; Weber, I. T. Novel P2 tris-tetrahydrofuran group in antiviral compound 1 (GRL0519) fills the S2 binding pocket of selected mutants of HIV-1 protease. J. Med. Chem. 2013, 56, 1074– 1083, DOI: 10.1021/jm301519z[ACS Full Text.], [CAS], Google Scholar163bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXkt1yhtg%253D%253D&md5=85fbfa86a8f494f6d4925ecf336610afNovel P2 Tris-tetrahydrofuran Group in Antiviral Compound 1 (GRL-0519) Fills the S2 Binding Pocket of Selected Mutants of HIV-1 ProteaseZhang, Hongmei; Wang, Yuan-Fang; Shen, Chen-Hsiang; Agniswamy, Johnson; Rao, Kalapala Venkateswara; Xu, Chun-Xiao; Ghosh, Arun K.; Harrison, Robert W.; Weber, Irene T.Journal of Medicinal Chemistry (2013), 56 (3), 1074-1083CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)GRL-0519 is a potent antiviral inhibitor of HIV-1 protease (PR) possessing tris-tetrahydrofuran (tris-THF) at P2. The high resoln. X-ray crystal structures of inhibitor in complexes with single substitution mutants PRR8q, PRD30N, PRI50V, PRI54M, and PRV82A were analyzed in relation to kinetic data. The smaller valine side chain in PRI50V eliminated hydrophobic interactions with inhibitor and the other subunit consistent with 60-fold worse inhibition. Asn30 in PRD30N showed altered interactions with neighboring residues and 18-fold worse inhibition. Mutations V82A and I54M showed compensating structural changes consistent with 6-7-fold lower inhibition. Gln8 in PRR8q replaced the ionic interactions of wild type Arg8 with hydrogen bond interactions without changing the inhibition significantly. The carbonyl oxygen of Gly48 showed two alternative conformations in all structures likely due to the snug fit of the large tris-THF group in the S2 subsite in agreement with high antiviral efficacy of 1 on resistant virus.(c) Ghosh, A. K.; Rao, K. V.; Nyalapatla, P. R.; Osswald, H. L.; Martyr, C. D.; Aoki, M.; Hayashi, H.; Agniswamy, J.; Wang, Y.; Bulut, H.; Das, D.; Weber, I. T.; Mitsuya, H. Design and development of highly potent HIV-1 protease inhibitors with a crown-like oxotricyclic core as the P2-ligand to combat multidrug-resistant HIV variants. J. Med. Chem. 2017, 60, 4267– 4278, DOI: 10.1021/acs.jmedchem.7b00172[ACS Full Text], [CAS], Google Scholar163chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXmtFKlsLw%253D&md5=03b84db839ddd5d19195e5dd8bf43642Design and Development of Highly Potent HIV-1 Protease Inhibitors with a Crown-Like Oxotricyclic Core as the P2-Ligand To Combat Multidrug-Resistant HIV VariantsGhosh, Arun K.; Rao, Kalapala Venkateswara; Nyalapatla, Prasanth R.; Osswald, Heather L.; Martyr, Cuthbert D.; Aoki, Manabu; Hayashi, Hironori; Agniswamy, Johnson; Wang, Yuan-Fang; Bulut, Haydar; Das, Debananda; Weber, Irene T.; Mitsuya, HiroakiJournal of Medicinal Chemistry (2017), 60 (10), 4267-4278CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Design, synthesis, and evaluation of a new class of exceptionally potent HIV-1 protease inhibitors is reported. Inhibitor I displayed superior antiviral activity and drug-resistance profiles. In fact, this inhibitor showed several orders of magnitude improved antiviral activity over the FDA approved drug, darunavir. This inhibitor incorporates an unprecedented 6-5-5 ring-fused crown-like tetrahydropyranofuran as the P2 ligand and an aminobenzothiazole as the P2' ligand with the (R)-hydroxyethylsulfonamide isostere. The crown-like P2 ligand for this inhibitor has been synthesized efficiently in an optically active form using a chiral Diels-Alder catalyst providing a key intermediate in high enantiomeric purity. Two high resoln. X-ray structures of inhibitor-bound HIV-1 protease revealed extensive interactions with the backbone atoms of HIV-1 protease and provided mol. insight into the binding properties of these new inhibitors.
- 164(a) Chang, Z. The discovery of Qinghaosu (artemisinin) as an effective anti-malaria drug: A unique China story. Sci. China: Life Sci. 2016, 59, 81– 88, DOI: 10.1007/s11427-015-4988-z[Crossref], [PubMed], [CAS], Google Scholar.164ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28vpvVynuw%253D%253D&md5=577bcc8d1c235623b7c436325f7227a2The discovery of Qinghaosu (artemisinin) as an effective anti-malaria drug: A unique China storyChang ZengyiScience China. Life sciences (2016), 59 (1), 81-8 ISSN:.There is no expanded citation for this reference.(b) Cui, L.; Su, X. Discovery, mechanisms of action and combination therapy of artemisinin. Expert Rev. Anti-Infect. Ther. 2009, 7, 999– 1013, DOI: 10.1586/eri.09.68[Crossref], [PubMed], [CAS], Google Scholar.164bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXht1Wru7fM&md5=29fb8392d6b533f4073e958eab1fe1f9Discovery, mechanisms of action and combination therapy of artemisininCui, Li-Wang; Su, Xin-ZhuanExpert Review of Anti-Infective Therapy (2009), 7 (8), 999-1013CODEN: ERATCK; ISSN:1478-7210. (Expert Reviews Ltd.)A review. Despite great international efforts, malaria still inflicts an enormous toll on human lives, esp. in Africa. Throughout history, antimalarial medicines have been one of the most powerful tools in malaria control. However, the acquisition and spread of parasite strains that are resistant to multiple antimalarial drugs have become one of the greatest challenges to malaria treatment, and are assocd. with the increase in morbidity and mortality in many malaria-endemic countries. To deal with this grave situation, artemisinin-based combinatory therapies (ACTs) have been introduced and widely deployed in malarious regions. Artemisinin is a new class of antimalarial compds. discovered by Chinese scientists from the sweet wormwood Artemisia annua. The potential development of resistance to artemisinins by Plasmodium falciparum threatens the usable lifespan of ACTs, and therefore is a subject of close surveillance and extensive research. Studies at the Thai-Cambodian border, a historical epicenter of multidrug resistance, have detected reduced susceptibility to artemisinins as manifested by prolonged parasite-clearance times, raising considerable concerns on resistance development. Despite this significance, there is still controversy on the mode of action of artemisinins. Although a no. of potential cellular targets of artemisinins have been proposed, they remain to be verified exptl. Here, we review the history of artemisinin discovery, discuss the mode of action and potential drug targets, and present strategies to elucidate resistance mechanisms.(c) Fernández-Álvaro, E.; Hong, W. D.; Nixon, G. L.; O’Neill, P. M.; Calderón, F. Antimalarial chemotherapy: natural product inspired development of preclinical and clinical candidates with diverse mechanisms of action. J. Med. Chem. 2016, 59, 5587– 5603, DOI: 10.1021/acs.jmedchem.5b01485[ACS Full Text.], [CAS], Google Scholar164chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xht1aht7Y%253D&md5=993e5139a177a86e47dff4330b986bffAntimalarial Chemotherapy: Natural Product Inspired Development of Preclinical and Clinical Candidates with Diverse Mechanisms of ActionFernandez-Alvaro, Elena; Hong, W. David; Nixon, Gemma L.; O'Neill, Paul M.; Calderon, FelixJournal of Medicinal Chemistry (2016), 59 (12), 5587-5603CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Natural products have played a pivotal role in malaria chemotherapy progressing from quinine and artemisinin to ozonide-based compds. Many of these natural products have served as template for the design and development of antimalarial drugs currently in the clinic or in the development phase. In this review, we will detail those privileged scaffolds that have guided medicinal chem. efforts yielding mols. that have reached the clinic.(d) Wells, T. N.; Huijsduijnen, R. H.; Voorhis, W. C. Malaria medicines: a glass half full?. Nat. Rev. Drug Discovery 2015, 14, 424– 442, DOI: 10.1038/nrd4573[Crossref], [PubMed], [CAS], Google Scholar.164dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFemsbvM&md5=43f35590f86c240a4150b5cb4f5670adMalaria medicines: a glass half full?Wells, Timothy N. C.; Hooft van Huijsduijnen, Rob; Van Voorhis, Wesley C.Nature Reviews Drug Discovery (2015), 14 (6), 424-442CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)A review. Despite substantial scientific progress over the past two decades, malaria remains a worldwide burden that causes hundreds of thousands of deaths every year. New, affordable and safe drugs are required to overcome increasing resistance against artemisinin-based treatments, treat vulnerable populations, interrupt the parasite life cycle by blocking transmission to the vectors, prevent infection and target malaria species that transiently remain dormant in the liver. In this Review, we discuss how the antimalarial drug discovery pipeline has changed over the past 10 years, grouped by the various target compd. or product profiles, to assess progress and gaps, and to recommend priorities.(e) Sharma, B.; Singh, P.; Singh, A. K.; Awasthi, S. K. Advancement of chimeric hybrid drugs to cure malaria infection: an overview with special emphasis on endoperoxide pharmacophores. Eur. J. Med. Chem. 2021, 219, 113408, DOI: 10.1016/j.ejmech.2021.113408[Crossref], [PubMed], [CAS], Google Scholar164ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhtFShu7fP&md5=5372f0027e4ac4114d766bc725be222eAdvancement of chimeric hybrid drugs to cure malaria infection: An overview with special emphasis on endoperoxide pharmacophoresSharma, Bhawana; Singh, Preeti; Singh, Ashawani Kumar; Awasthi, Satish K.European Journal of Medicinal Chemistry (2021), 219 (), 113408CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)Emergence and spread of Plasmodium falciparum resistant to artemisinin-based combination therapy has led to a situation of haste in the scientific and pharmaceutical communities. Sincere efforts are redirected towards finding alternative chemotherapeutic agents that are capable of combating multidrug-resistant parasite strains. Extensive research yielded the concept of "Chimeric Bitherapy (CB)" which involves the linking of two mols. with individual pharmacol. activity and exhibit dual mode of action into a single hybrid mol. Current research in this field seems to endorse hybrid mols. as the next-generation antimalarial drugs and are more effective compared to the multi-component drugs because of the lower occurrence of drug-drug adverse effects. This review is an attempt to congregate complete survey on endoperoxide based hybrid antiplasmodial mols. that will give glimpse on the future directions for successful development and discovery of useful antimalarial hybrid drugs.
- 165(a) Zeng, M.; Li, L.; Chen, S.; Li, C.; Liang, X.; Chen, M.; Clardy, J. Chemical transformations of qinghaosu, a peroxidic antimalarial. Tetrahedron 1983, 39, 2941– 2946, DOI: 10.1016/S0040-4020(01)92155-6[Crossref], [CAS], Google Scholar.165ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL2cXmtFym&md5=0a457679a176c87a49346bc6ac347effChemical transformations of qinghaosu, a peroxidic antimalarialZeng, Meiyi; Li, Lanna; Chen, Shufeng; Li, Guangyi; Liang, Xiaotian; Chen, Marie; Clardy, JonTetrahedron (1983), 39 (18), 2941-6CODEN: TETRAB; ISSN:0040-4020.The stereochem. is reported for 4 degrdn. products of the title compd. (I).(b) Lin, A. J.; Klayman, D. L.; Hoch, J. M.; Silverton, J. M.; George, C. F. Thermal rearrangement and decomposition products of artemisinin (qinghaosu). J. Org. Chem. 1985, 50, 4504– 4508, DOI: 10.1021/jo00223a017[ACS Full Text], [CAS], Google Scholar165bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL2MXlvFKhurw%253D&md5=98be39207f029e2ef2c431beb61b6b86Thermal rearrangement and decomposition products of artemisinin (qinghaosu)Lin, Ai Jeng; Klayman, Daniel L.; Hoch, James M.; Silverton, James V.; George, Clifford F.Journal of Organic Chemistry (1985), 50 (23), 4504-8CODEN: JOCEAH; ISSN:0022-3263.Thermal rearrangement and decompn. of artermisinin I on a silicone-oil bath preheated to 190° gave three major products II, III, and IV, whose structures were confirmed by x-ray anal.
- 166(a) Gomes, G.; Vil, V.; Terent’ev, A.; Alabugin, I. V. Stereoelectronic source of the anomalous stability of bis-peroxides. Chem. Sci. 2015, 6, 6783– 6791, DOI: 10.1039/C5SC02402A[Crossref], [PubMed], [CAS], Google Scholar.166ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVGisr3O&md5=e2a3658b0ed106108083b72ea1ece7efStereoelectronic source of the anomalous stability of bis-peroxidesGomes, Gabriel dos Passos; Vil', Vera; Terent'ev, Alexander; Alabugin, Igor V.Chemical Science (2015), 6 (12), 6783-6791CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)The unusual stability of bis- and tris-peroxides contradicts the conventional wisdom - some of them can melt without decompn. at temps. exceeding 100 °C. In this work, we disclose a stabilizing stereoelectronic effect that two peroxide groups can exert on each other. This stabilization originates from strong anomeric nO → σ*CO interactions that are absent in mono-peroxides but reintroduced in mols. where two peroxide moieties are sepd. by a CH2 group. Furthermore, such effects can be induced by other σ-acceptors and amplified by structural constraints imposed by cyclic and bicyclic frameworks.(b) Edwards, J. O.; Pearson, R. G. The factors determining nucleophilic reactivities. J. Am. Chem. Soc. 1962, 84, 16– 24, DOI: 10.1021/ja00860a005[ACS Full Text.], [CAS], Google Scholar166bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF38XktlGrsbk%253D&md5=9380eb168691c157e8c03ab5119fcf41The factors determining nucleophilic reactivitiesEdwards, John O.; Pearson, Ralph G.Journal of the American Chemical Society (1962), 84 (1), 16-24CODEN: JACSAT; ISSN:0002-7863.The important factors influencing the reactivity of nucleophilie reagents in the general bimol. nucleophilic substitution reaction N + SX → NS + X are the basicity of N, polarizability of N, and the presence of unshared electron pairs on an atom adjacent to N (called here the α-effect). Basicity becomes an increasingly important factor in the rate of substitution as the pos. charge on S increases; polarizability is most effective when S is electroneg. and has many outer electrons; the α-effect is general for all substrates, SX. Rates of substitution of many nucleophiles on several substrates are tabulated and discussed. Basicity is the most important factor for substitution on carbonyl C, tetrahedral P, trigonal and tetrahedral B, tetrahedral S, and tetrahedral Cl; polarizability is a more important factor when S is Pt(II), HOO-, satd. C, covalent F, trivalent N; aromatic C and S(II) require both factors. The most polarizable reagents examd. were SC(NH2)2, I-, SO3--, S2O3--. The name biphilic agent is suggested for a polarizable nucleophile which donates electrons to S in a a bond and accepts electrons from S in a τ bond; examples are CO and trialkylphosphines.(c) Hoz, S.; Buncel, E. The α-effect: a critical examination of the phenomenon and its origin. Isr. J. Chem. 1985, 26, 313– 319, DOI: 10.1002/ijch.198500113[Crossref], [CAS], Google Scholar.166chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL28XlsFahtrg%253D&md5=11462fce7d52b0823e8c213b7535bd36The α-effect: a critical examination of the phenomenon and its originHoz, S.; Buncel, E.Israel Journal of Chemistry (1985), 26 (4), 313-19CODEN: ISJCAT; ISSN:0021-2148.A few aspects related to the nature and origin of the α-effect are reviewed with 54 refs.(d) Buncel, E.; Um, I. The α-effect and its modulation by solvent. Tetrahedron 2004, 60, 7801– 7825, DOI: 10.1016/j.tet.2004.05.006[Crossref], [CAS], Google Scholar166dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXmsVajtr4%253D&md5=519fbc0a9a68330c7b012922747db85eThe α-effect and its modulation by solventBuncel, Erwin; Um, Ik-HwanTetrahedron (2004), 60 (36), 7801-7825CODEN: TETRAB; ISSN:0040-4020. (Elsevier B.V.)A review. Although several reviews on the α-effect have been published previously, the effect of solvent on the α-effect has been neglected, probably due to a lack of relevant data on solvent effects at that time. The present review will mainly deal with the effect of solvent on the α-effect for various types of reactions, though factors influencing the magnitude of the α-effect will also be discussed.
- 167Haynes, R. K.; Krishna, S. Artemisinins: activities and actions. Microbes Infect. 2004, 6, 1339– 1346, DOI: 10.1016/j.micinf.2004.09.002[Crossref], [PubMed], [CAS], Google Scholar167https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhtVWitLzK&md5=b013c81ce6253e2f77e3a5cd1443c3a3Artemisinins: activities and actionsHaynes, Richard K.; Krishna, SanjeevMicrobes and Infection (2004), 6 (14), 1339-1346CODEN: MCINFS; ISSN:1286-4579. (Elsevier B.V.)A review. Multidrug-resistant malaria caused by Plasmodium falciparum has severely limited treatment options over recent years. Artemisinins are still effective for treating uncomplicated as well as severe malaria, because resistance is not yet clin. apparent. This article reviews some clin. useful properties of artemisinins and how they might work.
- 168(a) O’Neill, P. M.; Barton, V. E.; Ward, S. A. The molecular mechanism of action of artemisinin - the debate continues. Molecules 2010, 15, 1705– 1721, DOI: 10.3390/molecules15031705[Crossref], [PubMed], [CAS], Google Scholar.168ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXjs1ygurY%253D&md5=be4d50f93ea4c66578d5043f164dab31The molecular mechanism of action of artemisinin - the debate continuesO'Neill, Paul M.; Barton, Victoria E.; Ward, Stephen A.Molecules (2010), 15 (), 1705-1721CODEN: MOLEFW; ISSN:1420-3049. (Molecular Diversity Preservation International)A review. Despite international efforts to 'roll back malaria' the 2008 World Malaria Report revealed the disease still affects approx. 3 billion people in 109 countries; 45 within the WHO African region. The latest report however does provide some 'cautious optimism'; more than one-third of malarious countries have documented >50% redns. in malaria cases in 2008 compared to 2000. The goal of the Member States at the World Health Assembly and 'Roll Back Malaria' (RBM) partnership is to reduce the nos. of malaria cases and deaths recorded in 2000 by 50% or more by the end of 2010. Although malaria is preventable it is most prevalent in poorer countries where prevention is difficult and prophylaxis is generally not an option. The burden of disease has increased by the emergence of multi drug resistant (MDR) parasites which threatens the use of established and cost effective antimalarial agents. After a major change in treatment policies, artemisinins are now the frontline treatment to aid rapid clearance of parasitemia and quick resoln. of symptoms. Since artemisinin and its derivs. are eliminated rapidly, artemisinin combination therapies (ACT's) are now recommended to delay resistance mechanisms. In spite of these precautionary measures reduced susceptibility of parasites to the artemisinin-based component of ACT's has developed at the Thai-Cambodian border, a historical 'hot spot' for MDR parasite evolution and emergence. This development raises serious concerns for the future of the artemisinins and this is not helped by controversy related to the mode of action. Although a no. of potential targets were proposed the actual mechanism of action remains ambiguous. Interestingly, artemisinins have also shown potent and broad anticancer properties in cell lines and animal models and are becoming established as anti-schistosomal agents. In this review we will discuss the recent evidence explaining bioactivation and potential mol. targets in the chemotherapy of malaria and cancer.(b) Li, Z.; Li, Q.; Wu, J.; Wang, M.; Yu, J. Artemisinin and its derivatives as a repurposing anticancer agent: what else do we need to do?. Molecules 2016, 21, 1331, DOI: 10.3390/molecules21101331[Crossref], [CAS], Google Scholar.168bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhvFaksrvF&md5=e3edbb58fac695ecec98fc970448db96Artemisinin and its derivatives as a repurposing anticancer agent: what else do we need to do?Li, Zhe; Li, Qin; Wu, Jun; Wang, Manyuan; Yu, JunxianMolecules (2016), 21 (10), 1331/1-1331/14CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)Preclin. investigation and clin. experience have provided evidence on the potential anticancer effect of artemisinin and its derivs. (ARTs) in the recent two decades. The major mechanisms of action of ARTs may be due to toxic-free radicals generated by an endoperoxide moiety, cell cycle arrest, induction of apoptosis, and inhibition of tumor angiogenesis. It is very promising that ARTs are expected to be a new class of antitumor drugs of wide spectrum due to their detailed information regarding efficacy and safety. For developing repurposed drugs, many other characteristics of ARTs should be studied, including through further investigations on possible new pathways of anticancer effects, exploration on efficient and specific drug delivery systems-esp. crossing biol. barriers, and obtaining sufficient data in clin. trials. The aim of this review is to highlight these achievements and propose the potential strategies to develop ARTs as a new class of cancer therapeutic agents.(c) Cui, L.; Su, X. Z. Discovery, mechanisms of action and combination therapy of artemisinin. Expert Rev. Anti-Infect. Ther. 2009, 7, 999– 1013, DOI: 10.1586/eri.09.68[Crossref], [PubMed], [CAS], Google Scholar.168chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXht1Wru7fM&md5=29fb8392d6b533f4073e958eab1fe1f9Discovery, mechanisms of action and combination therapy of artemisininCui, Li-Wang; Su, Xin-ZhuanExpert Review of Anti-Infective Therapy (2009), 7 (8), 999-1013CODEN: ERATCK; ISSN:1478-7210. (Expert Reviews Ltd.)A review. Despite great international efforts, malaria still inflicts an enormous toll on human lives, esp. in Africa. Throughout history, antimalarial medicines have been one of the most powerful tools in malaria control. However, the acquisition and spread of parasite strains that are resistant to multiple antimalarial drugs have become one of the greatest challenges to malaria treatment, and are assocd. with the increase in morbidity and mortality in many malaria-endemic countries. To deal with this grave situation, artemisinin-based combinatory therapies (ACTs) have been introduced and widely deployed in malarious regions. Artemisinin is a new class of antimalarial compds. discovered by Chinese scientists from the sweet wormwood Artemisia annua. The potential development of resistance to artemisinins by Plasmodium falciparum threatens the usable lifespan of ACTs, and therefore is a subject of close surveillance and extensive research. Studies at the Thai-Cambodian border, a historical epicenter of multidrug resistance, have detected reduced susceptibility to artemisinins as manifested by prolonged parasite-clearance times, raising considerable concerns on resistance development. Despite this significance, there is still controversy on the mode of action of artemisinins. Although a no. of potential cellular targets of artemisinins have been proposed, they remain to be verified exptl. Here, we review the history of artemisinin discovery, discuss the mode of action and potential drug targets, and present strategies to elucidate resistance mechanisms.(d) Wang, J.; Zhang, C. J.; Chia, W.; Loh, C.; Li, Z.; Lee, Y. M.; He, Y.; Yuan, L. X.; Lim, T. K.; Liu, M.; Liew, C. X.; Lee, Y. Q.; Zhang, J.; Lu, N.; Lim, C. T.; Hua, Z. C.; Liu, B.; Shen, H. M.; Tan, K. S.; Lin, Q. Haem-activated promiscuous targeting of artemisinin in Plasmodium falciparum. Nat. Commun. 2015, 6, 10111, DOI: 10.1038/ncomms10111[Crossref], [PubMed], [CAS], Google Scholar168dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXitVynsLjO&md5=a532a76cdd2f33b0ca23e733e6247a0cHaem-activated promiscuous targeting of artemisinin in Plasmodium falciparumWang, Jigang; Zhang, Chong-Jing; Chia, Wan Ni; Loh, Cheryl C. Y.; Li, Zhengjun; Lee, Yew Mun; He, Yingke; Yuan, Li-Xia; Lim, Teck Kwang; Liu, Min; Liew, Chin Xia; Lee, Yan Quan; Zhang, Jianbin; Lu, Nianci; Lim, Chwee Teck; Hua, Zi-Chun; Liu, Bin; Shen, Han-Ming; Tan, Kevin S. W.; Lin, QingsongNature Communications (2015), 6 (), 10111CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)The mechanism of action of artemisinin and its derivs., the most potent of the anti-malarial drugs, is not completely understood. Here we present an unbiased chem. proteomics anal. to directly explore this mechanism in Plasmodium falciparum. We use an alkyne-tagged artemisinin analog coupled with biotin to identify 124 artemisinin covalent binding protein targets, many of which are involved in the essential biol. processes of the parasite. Such a broad targeting spectrum disrupts the biochem. landscape of the parasite and causes its death. Furthermore, using alkyne-tagged artemisinin coupled with a fluorescent dye to monitor protein binding, we show that haem, rather than free ferrous iron, is predominantly responsible for artemisinin activation. The haem derives primarily from the parasite's haem biosynthesis pathway at the early ring stage and from Hb digestion at the latter stages. Our results support a unifying model to explain the action and specificity of artemisinin in parasite killing.
- 169(a) Lin, A. J.; Klayman, D. L.; Milhous, W. K. Antimalarial activity of new water-soluble dihydroartemisinin derivatives. J. Med. Chem. 1987, 30, 2147– 2150, DOI: 10.1021/jm00394a037[ACS Full Text.], [CAS], Google Scholar169ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL2sXls1yhtr8%253D&md5=0de274333c579fc93e5797fb08adefb9Antimalarial activity of new water-soluble dihydroartemisinin derivativesLin, Ai Jeng; Klayman, Daniel L.; Milhous, Wilbur K.Journal of Medicinal Chemistry (1987), 30 (11), 2147-50CODEN: JMCMAR; ISSN:0022-2623.The title derivs. were prepd. in good yield by treatment of dihydroartemisinin with an appropriate alc. under BF3 etherate catalysis at room temp. All major condensation products were the β isomer. Hydrolysis of the esters with 2.5% KOH/MeOH gave the corresponding K salts, which were converted to free acids (I; R = CO2H or 4-C6H4CO2H and n = 1-3) by acidification. The derivs. were tested in vitro against two clones of human malaria, Plasmodium falciparum D-6 (Sierra Leone clone) and W-2 (Indochina clone). No cross-resistance to the antimalarial agents mefloquine, chloroquine, pyrimethamine, sulfadoxine, and quinine was obsd. In general, the new compds. are more effective against the W-2 than the D-6 strain. Various I esters possessed activity comparable to that of the parent compds. artemisinin and dihydroartemisinin; however, conversion of the esters to their corresponding carboxylates or acids with the exception of artelinic acid (I; R = 4-C6H4CO2H and n = 1), drastically decreased the antimalarial activities in both cell lines. Artelinic acid, which is both water sol. and stable in 2.5% K2CO3 soln., possessed superior in vivo activity against P. berghei than artemisinin or artesunic acid.(b) Lin, A. J.; Zikry, A. B.; Kyle, D. E. Antimalarial activity of new dihydroartemisinin derivatives. 7. 4-(p-Substituted phenyl)-4(R or S)-[10(δ. or β)-dihydroartemisininoxy]butyric acids. J. Med. Chem. 1997, 40, 1396– 1400, DOI: 10.1021/jm9607919[ACS Full Text], [CAS], Google Scholar169bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXitlWjsLo%253D&md5=9271fa56f9a40e9a6e6866907f3e2a64Antimalarial Activity of New Dihydroartemisinin Derivatives. 7. 4-(p-Substituted phenyl)-4(R or S)-[10(α or β)-dihydroartemisininoxy]butyric AcidsLin, Ai J.; Zikry, Akram B.; Kyle, Dennis E.Journal of Medicinal Chemistry (1997), 40 (9), 1396-1400CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)To search for water sol. dihydroartemisinin derivs. with higher efficacy and longer plasma half-life than artesunic or artelinic acid, a series of new stereoisomers of 4-(p-substituted phenyl)-4(R or S)-[10(α or β)-dihydroartemisininoxy]butyric acids were synthesized as new potential antimalarial agents. Two approaches were taken in the design of these new mols. to (a) increase the lipophilicity of the mol. and (b) decrease the rate of oxidative dealkylation of the target compds. The new compds. showed a 2-10-fold increase in in vitro antimalarial activity against D-6 and W-2 clones of Plasmodium falciparum than artemisinin or artelinic acid. R-diastereomers are, in general, more potent than the corresponding S-diastereomers. P-Chlorophenyl and p-bromophenyl derivs. showed in vivo oral antimalarial activity against P. berghei (with 3/8 cured) superior to that of artelinic acid (1/8 cured), whereas p-fluorophenyl and p-methoxyphenyl analogs demonstrated activity only comparable (1/8 cured) to that of artelinic acid at the same dosage level (64 mg/kg twice a day). The in vivo antimalarial activity of these new compds. correlates with their SD50 (50% parasitemia suppression dose). The biol. results suggested that an electronic effect, besides the lipophilicity, may play a role in detg. the efficacy of this class of compds.
- 170Jung, M.; Lee, S. Stability of acetal and non acetal-type analogues of artemisinin in simulated stomach acid. Bioorg. Med. Chem. Lett. 1998, 8, 1003– 1006, DOI: 10.1016/S0960-894X(98)00160-7[Crossref], [PubMed], [CAS], Google Scholar170https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXjtlSntL4%253D&md5=711a622e9d4a075defeb6f27fe7fe71bStability of acetal and non acetal-type analogs of artemisinin in simulated stomach acidJung, Mankil; Lee, SeokjoonBioorganic & Medicinal Chemistry Letters (1998), 8 (9), 1003-1006CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)A series of non acetal-type analogs of artemisinin contg. C-C bond at position-12 have been found to be 15 - 22 times more stable than acetal(C-O)-type prodrugs of artemisinin in simulated stomach acid.
- 171Jung, M.; Lee, K.; Kendrick, H.; Robinson, B. L.; Croft, S. L. Synthesis, stability, and antimalarial activity of new hydrolytically stable and water-soluble (+)-deoxoartelinic acid. J. Med. Chem. 2002, 45, 4940– 4944, DOI: 10.1021/jm020244p[ACS Full Text], [CAS], Google Scholar171https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XmvVShsLs%253D&md5=b302136bb6adc609ea0f7dd91685fd84Synthesis, Stability, and Antimalarial Activity of New Hydrolytically Stable and Water-Soluble (+)-Deoxoartelinic AcidJung, Mankil; Lee, Kyunghoon; Kendrick, Howard; Robinson, Brian L.; Croft, Simon L.Journal of Medicinal Chemistry (2002), 45 (22), 4940-4944CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)(+)-Deoxoartelinic acid (I), a new hydrolytically stable, water-sol., and potent non-acetal-type antimalarial drug candidate, was successfully prepd. from artemisinic acid by using sulfur ylide and photooxygenative cyclization in seven steps. I showed superior in vitro antimalarial activity against the chloroquine-resistant K1 strain of Plasmodium falciparum and higher suppression (98.7%) than arteether in vivo against Plasmodium chabaudi infected mice. I also showed remarkable stability with a half-life of 258.66 h, 23 times more stable than clin. useful arteether in simulated stomach acid, and improved soly., 4 times more sol. than artemisinin in water.
- 172Singh, C.; Verma, V. P.; Hassam, M.; Singh, A. S.; Naikade, N. K.; Puri, S. K. New orally active amino- and hydroxy-functionalized 11-azaartemisinins and their derivatives with high order of antimalarial activity against multidrug-resistant Plasmodium yoelii in Swiss mice. J. Med. Chem. 2014, 57, 2489– 2497, DOI: 10.1021/jm401774f[ACS Full Text], [CAS], Google Scholar172https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXisFKhs7k%253D&md5=e4518e78d108f4e688956f7afdd30357New Orally Active Amino- and Hydroxy-Functionalized 11-Azaartemisinins and Their Derivatives with High Order of Antimalarial Activity against Multidrug-Resistant Plasmodium yoelii in Swiss MiceSingh, Chandan; Verma, Ved Prakash; Hassam, Mohammad; Singh, Ajit Shankar; Naikade, Niraj K.; Puri, Sunil K.Journal of Medicinal Chemistry (2014), 57 (6), 2489-2497CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)By use of artemisinin as the starting material, two new amino- and hydroxy-functionalized 11-azaartemisinins and their derivs. have been prepd. and screened for antimalarial activity by oral route against multidrug-resistant Plasmodium yoelii in Swiss mice. While N-amino- and N-hydroxy- 11-azaartemisinin showed only modest activity, several of their derivs. showed high order of antimalarial activity. Biphenyl-based compd. I, the most active compd. of the series, provided 100% and 80% protection to the infected mice at 12 mg/kg × 4 days and 6 mg/kg × 4 days, resp. Some compds. showed 100% protection at 12 mg/kg × 4 days, while other compds. showed similar levels of protection at 24 mg/kg × 4 days. Clin. useful drug β-arteether provided 100% protection at 48 mg/kg × 4 days and 20% protection at 24 mg/kg × 4 days in this model.
- 173Haynes, R. K.; Fugmann, B.; Stetter, J.; Rieckmann, K.; Heilmann, H.; Chan, H.; Cheung, M.; Lam, W.; Wong, H.; Croft, S. L.; Vivas, L.; Rattray, L.; Stewart, L.; Peters, W.; Robinson, B. L.; Edstein, M. D.; Kotecka, B.; Kyle, D. E.; Beckermann, B.; Gerisch, M.; Radtke, M.; Schmuck, G.; Steinke, W.; Wollborn, U.; Schmeer, K.; Romer, A. Artemisone - a highly active antimalarial drug of the artemisinin class. Angew. Chem., Int. Ed. 2006, 45, 2082– 2088, DOI: 10.1002/anie.200503071[Crossref], [CAS], Google Scholar173https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xjt1Ogs7s%253D&md5=00e60d8f412ecadc851db62a87e4a9c9Artemisone - a highly active antimalarial drug of the artemisinin classHaynes, Richard K.; Fugmann, Burkhard; Stetter, Jorg; Rieckmann, Karl; Heilmann, Hans-Dietrich; Chan, Ho-Wai; Cheung, Man-Ki; Lam, Wai-Lun; Wong, Ho-Ning; Croft, Simon L.; Vivas, Livia; Rattray, Lauren; Stewart, Lindsay; Peters, Wallace; Robinson, Brian L.; Edstein, Michael D.; Kotecka, Barbara; Kyle, Dennis E.; Beckermann, Bernhard; Gerisch, Michael; Radtke, Martin; Schmuck, Gabriele; Steinke, Wolfram; Wollborn, Ute; Schmeer, Karl; Romer, AxelAngewandte Chemie, International Edition (2006), 45 (13), 2082-2088CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)Efficacies of artemisone (I) against malaria parasites are substantially greater than those of the current artemisinin "gold std.", artesunate. In contrast to most current artemisinins, I displays low lipophilicity and negligible neuro- and cytotoxicity in in vitro and in vivo assays. Thus, the drug offers promise for use in artemisinin-based combination therapy.
- 174Wang, X.; Dong, Y.; Wittlin, S.; Charman, S. A.; Chiu, F. C.; Chollet, J.; Katneni, K.; Mannila, J.; Morizzi, J.; Ryan, E.; Scheurer, C.; Steuten, J.; Tomas, J. S.; Snyder, C.; Vennerstrom, J. L. Comparative antimalarial activities and ADME profiles of ozonides (1,2,4-trioxolanes) OZ277, OZ439, and their 1,2-dioxolane, 1,2,4-trioxane, and 1,2,4,5-tetraoxane isosteres. J. Med. Chem. 2013, 56, 2547– 2555, DOI: 10.1021/jm400004u[ACS Full Text], [CAS], Google Scholar174https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXktVCksb0%253D&md5=ebba930db3a19ccb90bc8feb57389972Comparative Antimalarial Activities and ADME Profiles of Ozonides (1,2,4-trioxolanes) OZ277, OZ439, and Their 1,2-Dioxolane, 1,2,4-Trioxane, and 1,2,4,5-Tetraoxane IsosteresWang, Xiaofang; Dong, Yuxiang; Wittlin, Sergio; Charman, Susan A.; Chiu, Francis C. K.; Chollet, Jacques; Katneni, Kasiram; Mannila, Janne; Morizzi, Julia; Ryan, Eileen; Scheurer, Christian; Steuten, Jessica; Santo Tomas, Josefina; Snyder, Christopher; Vennerstrom, Jonathan L.Journal of Medicinal Chemistry (2013), 56 (6), 2547-2555CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)To ascertain the structure-activity relationship of the core 1,2,4-trioxolane substructure of dispiro ozonides OZ277 and OZ439, we compared the antimalarial activities and ADME profiles of the 1,2-dioxolane, 1,2,4-trioxane, and 1,2,4,5-tetraoxane isosteres. Consistent with previous data, both dioxolanes had very weak antimalarial properties. For the OZ277 series, the trioxane isostere had the best ADME profile, but its overall antimalarial efficacy was not superior to that of the trioxolane or tetraoxane isosteres. For the OZ439 series, there was a good correlation between the antimalarial efficacy and ADME profiles in the rank order trioxolane > trioxane > tetraoxane. As we have previously obsd. for OZ439 vs. OZ277, the OZ439 series peroxides had superior exposure and efficacy in mice compared to the corresponding OZ277 series peroxides.
- 175(a) Benoit-Vical, F.; Lelievre, J.; Berry, A.; Deymier, C.; Dechy-Cabaret, O.; Cazelles, J.; Loup, C.; Robert, A.; Magnaval, J.; Meunier, B. Trioxaquines are new antimalarial agents active on all erythrocytic forms, including gametocytes. Antimicrob. Agents Chemother. 2007, 51, 1463– 1472, DOI: 10.1128/AAC.00967-06[Crossref], [PubMed], [CAS], Google Scholar.175ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXktlOjtbg%253D&md5=a9ed6a6d13c3cb9e6e7991ef02daf578Trioxaquines are new antimalarial agents active on all erythrocytic forms, including gametocytesBenoit-Vical, Francoise; Lelievre, Joel; Berry, Antoine; Deymier, Caroline; Dechy-Cabaret, Odile; Cazelles, Jerome; Loup, Christophe; Robert, Anne; Magnaval, Jean-Francois; Meunier, BernardAntimicrobial Agents and Chemotherapy (2007), 51 (4), 1463-1472CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)Malaria is the third most significant cause of infectious disease in the world. The search for new antimalarial chemotherapy has become increasingly urgent due to parasite resistance to classical drugs. Trioxaquines are synthetic hybrid mols. contg. a trioxane motif (which is responsible for the antimalarial activity of artemisinin) linked to an aminoquinoline entity (which is responsible for the antiplasmodial properties of chloroquine). These trioxaquines are highly potent against young erythrocytic stages of Plasmodium falciparum and exhibit efficient activity in vitro against chloroquine-sensitive and -resistant strains of P. falciparum (50% inhibitory concn., 4 to 32 nM) and are also active in vivo against P. vinckei petteri and P. yoelii nigeriensis in suppressive and curative murine tests. The trioxaquine DU1302 is one of these promising antimalarial agents. The present study confirms the absence of toxicity of this drug on cell lines and in a mice model. Moreover, DU1302 exhibits potent activity against gametocytes, the form transmitted by mosquitoes, as killing of the gametocytes is essential to limit the spread of malaria. The ease of chem. synthesis of this trioxaquine prototype should be considered an addnl. advantage and would make these drugs affordable without perturbations of the drug supply.(b) Cosledan, F.; Fraisse, L.; Pellet, A.; Guillou, F.; Mordmuller, B.; Kremsner, P. G.; Moreno, A.; Mazier, D.; Maffrand, J.-P.; Meunier, B. Selection of a trioxaquine as an antimalarial drug candidate. Proc. Natl. Acad. Sci. U. S. A. 2008, 105, 17579– 17584, DOI: 10.1073/pnas.0804338105[Crossref], [PubMed], [CAS], Google Scholar.175bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsVWntbnP&md5=779ad725de8eb3f7fb528fd5aa0e71fdSelection of a trioxaquine as an antimalarial drug candidateCosledan, Frederic; Fraisse, Laurent; Pellet, Alain; Guillou, Francois; Mordmueller, Benjamin; Kremsner, Peter G.; Moreno, Alicia; Mazier, Dominique; Maffrand, Jean-Pierre; Meunier, BernardProceedings of the National Academy of Sciences of the United States of America (2008), 105 (45), 17579-17584CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Trioxaquines are antimalarial agents based on hybrid structures with a dual mode of action. One of these mols., PA1103/SAR116242, is highly active in vitro on several sensitive and resistant strains of Plasmodium falciparum at nanomolar concns. (e.g., IC50 value = 10 nM with FcM29, a chloroquine-resistant strain) and also on multidrug-resistant strains obtained from fresh patient isolates in Gabon. This mol. is very efficient by oral route with a complete cure of mice infected with chloroquine-sensitive or chloroquine-resistant strains of Plasmodia at 26-32 mg/kg. This compd. is also highly effective in humanized mice infected with P. falciparum. Combined with a good drug profile (preliminary absorption, metab., and safety parameters), these data were favorable for the selection of this particular trioxaquine for development as drug candidate among 120 other active hybrid mols.(c) Waseem, Y.; Hasan, C. A.; Ahmed, F. Artemisinin: A promising adjunct for cancer therapy. Cureus. 2018, 10 (11), e3628 DOI: 10.7759/cureus.3628 .(d) Fröhlich, T.; Çapcı, K. A.; Reiter, C.; Tsogoeva, S. B. Artemisinin-derived dimers: potent antimalarial and anticancer agents. J. Med. Chem. 2016, 59 (16), 7360– 88, DOI: 10.1021/acs.jmedchem.5b01380[ACS Full Text.], [CAS], Google Scholar175dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28fjtlKhsA%253D%253D&md5=0bc32b707e395961bf4a61a2c0665061Artemisinin-Derived Dimers: Potent Antimalarial and Anticancer AgentsFrohlich Tony; Capci Karagoz Aysun; Reiter Christoph; Tsogoeva Svetlana BJournal of medicinal chemistry (2016), 59 (16), 7360-88 ISSN:.The development of new efficient therapeutics for the treatment of malaria and cancer is an important endeavor. Over the past 15 years, much attention has been paid to the synthesis of dimeric structures, which combine two units of artemisinin, as lead compounds of interest. A wide variety of atemisinin-derived dimers containing different linkers demonstrate improved properties compared to their parent compounds (e.g., circumventing multidrug resistance), making the dimerization concept highly compelling for development of efficient antimalarial and anticancer drugs. The present Perspective highlights recent developments on different types of artemisinin-derived dimers and their structural and functional features. Particular emphasis is put on the respective in vitro and in vivo studies, exploring the role of the length and nature of linkers on the activities of the dimers, and considering the future prospects of the dimerization concept for drug discovery.(e) Singh, N. P.; Lai, H. C.; Park, J. S.; Gerhardt, T. E.; Kim, B. J.; Wang, S.; Sasaki, T. Effects of artemisinin dimers on rat breast cancer cells in vitro and in vivo. Anticancer Res. 2011, 31 (12), 4111– 4[PubMed], [CAS], Google Scholar.175ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsFCmurk%253D&md5=70fcb4c00d0a68578d167f666db5e7a0Effects of artemisinin dimers on rat breast cancer cells in vitro and in vivoSingh, Narendra P.; Lai, Henry C.; Park, Ji Sun; Gerhardt, Thomas E.; Kim, Byung Ju; Wang, Shusheng; Sasaki, TomikazuAnticancer Research (2011), 31 (12), 4111-4114CODEN: ANTRD4; ISSN:0250-7005. (International Institute of Anticancer Research)Artemisinin has been shown to be an effective antimalarial and anticancer compd. Dimers of artemisinin have been synthesized and shown to be potent antimalarials compared with monomers. In the present study, we investigated the effect of two artemisinin dimers (dimer-alc. and dimer-hydrazone) on rat mammary adeno-carcinoma cells (MTLn3) in vitro and in vivo compared with that of the artemisinin monomer dihydroartemisinin (DHA). We found that the dimers are considerably more potent than DHA in killing MTLn3 cells in vitro and suppressing the growth of MTLn3 breast tumors in vivo.(f) Moses, B. S.; McCullough, S.; Fox, J. M.; Mott, B. T.; Bentzen, S. M.; Kim, M.; Tyner, J. W.; Lapidus, R. G.; Emadi, A.; Rudek, M. A.; Kingsbury, T. J.; Civin, C. Antileukemic efficacy of a potent artemisinin combined with sorafenib and venetoclax. Blood Adv. 2021, 5 (3), 711– 724, DOI: 10.1182/bloodadvances.2020003429[Crossref], [PubMed], [CAS], Google Scholar.175fhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXnt1Sns7g%253D&md5=9d2906d8b1038d22d4537803e3151188Antileukemic efficacy of a potent artemisinin combined with sorafenib and venetoclaxMoses, Blake S.; McCullough, Samantha; Fox, Jennifer M.; Mott, Bryan T.; Bentzen, Soeren M.; Kim, MinJung; Tyner, Jeffrey W.; Lapidus, Rena G.; Emadi, Ashkan; Rudek, Michelle A.; Kingsbury, Tami J.; Civin, Curt I.Blood Advances (2021), 5 (3), 711-724CODEN: BALDBA; ISSN:2473-9537. (American Society of Hematology)Artemisinins are active against human leukemia cell lines and have low clin. toxicity in worldwide use as antimalarials. Because multiagent combination regimens are necessary to cure fully evolved leukemias, we sought to leverage our previous finding that artemisinin analogs synergize with kinase inhibitors, including sorafenib (SOR), by identifying addnl. synergistic antileukemic drugs with low toxicity. An oral 3-drug "SAV" regimen (SOR plus the potent artemisinin-derived trioxane diphenylphosphate 838 dimeric analog [ART838] plus VEN) killed leukemia cell lines and primary cells in vitro. Leukemia cells cultured in ART838 had decreased induced myeloid leukemia cell differentiation protein (MCL1) levels and increased levels of DNA damage-inducible transcript 3 (DDIT3; GADD153) mRNA and its encoded CCATT/enhancer-binding protein homologous protein (CHOP), a key component of the integrated stress response. Thus, synergy of the SAV combination may involve combined targeting of MCL1 and BCL2 via discrete, tolerable mechanisms, and cellular levels of MCL1 and DDIT3/CHOP may serve as biomarkers for action of artemisinins and SAV. Finally, SAV treatment was tolerable and resulted in deep responses with extended survival in 2 acute myeloid leukemia (AML) cell line xenograft models, both harboring a mixed lineage leukemia gene rearrangement and an FMS-like receptor tyrosine kinase-3 internal tandem duplication, and inhibited growth in 2 AML primagraft models.(g) Cheng, C.; Wang, T.; Song, Z.; Peng, L.; Gao, M.; Hermine, O.; Rousseaux, S.; Khochbin, S.; Mi, J. Q.; Wang, J. Induction of autophagy and autophagy-dependent apoptosis in diffuse large B-cell lymphoma by a new antimalarial artemisinin derivative, SM1044. Cancer Med. 2018, 7 (2), 380– 396, DOI: 10.1002/cam4.1276[Crossref], [PubMed], [CAS], Google Scholar175ghttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisVCitro%253D&md5=982b4862179ccc43b5983d6a77a7bb79Induction of autophagy and autophagy-dependent apoptosis in diffuse large B-cell lymphoma by a new antimalarial artemisinin derivative, SM1044Cheng, Chunyan; Wang, Tao; Song, Zhiqun; Peng, Lijun; Gao, Mengqing; Hermine, Olivier; Rousseaux, Sophie; Khochbin, Saadi; Mi, Jian-Qing; Wang, JinCancer Medicine (2018), 7 (2), 380-396CODEN: CMAEDL; ISSN:2045-7634. (John Wiley & Sons Ltd.)Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin's lymphoma. R-CHOP is currently the std. therapy for DLBCL, but the prognosis of refractory or recurrent patients remains poor. In this study, we synthesized a new water-sol. antimalarial drug artemisinin deriv., SM1044. The treatment of DLBCL cell lines with SM1044 induces autophagy-dependent apoptosis, which is directed by an accelerated degrdn. of the antiapoptosis protein Survivin, via its acetylation-dependent interaction with the autophagy-related protein LC3-II. Addnl., SM1044 also stimulates the de novo synthesis of ceramide, which in turn activates the CaMKK2-AMPK-ULK1 axis, leading to the initiation of autophagy. Our findings not only elucidate the mechanism of autophagy-dependent apoptosis in DLBCL cells, but also suggest that SM1044 is a promising therapeutic mol. for the treatment of DLBCL, along with R-CHOP regimen.
- 176(a) Vennerstrom, J. L.; Arbe-Barnes, S.; Brun, R.; Charman, S. A.; Chiu, F. C.; Chollet, J.; Dong, Y.; Dorn, A.; Hunziker, D.; Matile, H.; McIntosh, K.; Padmanilayam, M.; Tomas, J. S.; Scheurer, C.; Scorneaux, B.; Tang, Y.; Urwyler, H.; Wittlin, S.; Charman, W. N. Identification of an antimalarial synthetic trioxolane drugdevelopment candidate. Nature 2004, 430, 900– 904, DOI: 10.1038/nature02779[Crossref], [PubMed], [CAS], Google Scholar.176ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXmslCnurY%253D&md5=71070255d32c12fe3c227d5091225b31Identification of an antimalarial synthetic trioxolane drug development candidateVennerstrom, Jonathan L.; Arbe-Barnes, Sarah; Brun, Reto; Charman, Susan A.; Chiu, Francis C. K.; Chollet, Jacques; Dong, Yuxiang; Dorn, Arnulf; Hunziker, Daniel; Matile, Hugues; McIntosh, Kylie; Padmanilayam, Maniyan; Santo Tomas, Josefina; Scheurer, Christian; Scorneaux, Bernard; Tang, Yuanqing; Urwyler, Heinrich; Wittlin, Sergio; Charman, William N.Nature (London, United Kingdom) (2004), 430 (7002), 900-904CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)The discovery of artemisinin more than 30 yr ago provided a completely new antimalarial structural prototype; i.e., a mol. with a pharmacophoric peroxide bond in a unique 1,2,4-trioxane heterocycle. Available evidence suggests that artemisinin and related peroxidic antimalarial drugs exert their parasiticidal activity subsequent to reductive activation by hem, released as a result of Hb digestion by the malaria-causing parasite. This irreversible redox reaction produces carbon-centered free radicals, leading to alkylation of hem and proteins (enzymes), one of which-the sarcoplasmic-endoplasmic reticulum ATPase PfATP6 (ref. 7)-may be crit. to parasite survival. Notably, there is no evidence of drug resistance to any member of the artemisinin family of drugs. The chemotherapy of malaria has benefited greatly from the semi-synthetic artemisinins artemether and artesunate as they rapidly reduce parasite burden, have good therapeutic indexes and provide for successful treatment outcomes. However, as a drug class, the artemisinins suffer from chem. (semi-synthetic availability, purity and cost), biopharmaceutical (poor bioavailability and limiting pharmacokinetics) and treatment (noncompliance with long treatment regimens and recrudescence) issues that limit their therapeutic potential. Here the authors describe how a synthetic peroxide antimalarial drug development candidate was identified in a collaborative drug discovery project.(b) Dong, Y.; Tang, Y.; Chollet, J.; Matile, H.; Wittlin, S.; Charman, S. A.; Charman, W. N.; Tomas, J. S.; Scheurer, C.; Snyder, C. Effect of functional group polarity on the antimalarial activity of spiro and dispiro-1,2,4-trioxolanes. Bioorg. Med. Chem. 2006, 14, 6368– 6382, DOI: 10.1016/j.bmc.2006.05.041[Crossref], [PubMed], [CAS], Google Scholar.176bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XosVOhsLs%253D&md5=0e8953d3541244648820903c5756a9e8Effect of functional group polarity on the antimalarial activity of spiro and dispiro-1,2,4-trioxolanesDong, Yuxiang; Tang, Yuanqing; Chollet, Jacques; Matile, Hugues; Wittlin, Sergio; Charman, Susan A.; Charman, William N.; Tomas, Josefina Santo; Scheurer, Christian; Snyder, Christopher; Scorneaux, Bernard; Bajpai, Saroj; Alexander, Scott A.; Wang, Xiaofang; Padmanilayam, Maniyan; Cheruku, Srinivasa R.; Brun, Reto; Vennerstrom, Jonathan L.Bioorganic & Medicinal Chemistry (2006), 14 (18), 6368-6382CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)Based on the structures of several lipophilic trioxolane antimalarial prototypes, the authors set out to det. which functional groups were assocd. with good antimalarial profiles and identify more polar (lower Log P/Log D) lead compds. with good physicochem. properties. More lipophilic trioxolanes tended to have better oral activities than their more polar counterparts. Trioxolanes with a wide range of neutral and basic, but not acidic, functional groups had good antimalarial profiles.(c) Kim, H. S.; Hammill, J. T.; Guy, R. K. Seeking the elusive long-acting ozonide: discovery of artefenomel (OZ439). J. Med. Chem. 2017, 60, 2651– 2653, DOI: 10.1021/acs.jmedchem.7b00299[ACS Full Text.], [CAS], Google Scholar176chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXkt1Wktbo%253D&md5=e5c43979aaf0f7b6d0bce53c817cd733Seeking the Elusive Long-Acting Ozonide: Discovery of Artefenomel (OZ439)Kim, Ho Shin; Hammill, Jared T.; Guy, R. KiplinJournal of Medicinal Chemistry (2017), 60 (7), 2651-2653CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The majority of frontline therapies for the treatment of malaria are combination drugs contg. artemisinin (or its semisynthetic analogs), known as artemisinin combination therapies (ACTs). While generally efficacious, ACTs and the first generation fully synthetic ozonide, arterolane (OZ277, 1), suffer from rapid clearance requiring 3-day dosing regimens. Extensive structure-activity studies led to the discovery of a second-generation ozonide, artefenomel (OZ439, 2), which has overcome this limitation, maintaining the rapid onset of action and potent activity of the artemisinin derivs. while exhibiting greatly improved pharmacokinetics, low projected cost of goods, prophylactic activity, and the potential for a single dose cure.(d) Dong, Y.; Wang, X.; Kamaraj, S.; Bulbule, V. J.; Chiu, F. C.; Chollet, J.; Dhanasekaran, M.; Hein, C. D.; Papastogiannidis, P.; Morizzi, J.; Shackleford, D. M.; Barker, H.; Ryan, E.; Scheurer, C.; Tang, Y.; Zhao, Q.; Zhou, L.; White, K. L.; Urwyler, H.; Charman, W. N.; Matile, H.; Wittlin, S.; Charman, S. A.; Vennerstrom, J. L. Structure-activity relationship of the antimalarial ozonide artefenomel (OZ439). J. Med. Chem. 2017, 60, 2654– 2668, DOI: 10.1021/acs.jmedchem.6b01586[ACS Full Text.], [CAS], Google Scholar176dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXkslaitQ%253D%253D&md5=132212a3a83d1065f72151984f7c4c27Structure-Activity Relationship of the Antimalarial Ozonide Artefenomel (OZ439)Dong, Yuxiang; Wang, Xiaofang; Kamaraj, Sriraghavan; Bulbule, Vivek J.; Chiu, Francis C. K.; Chollet, Jacques; Dhanasekaran, Manickam; Hein, Christopher D.; Papastogiannidis, Petros; Morizzi, Julia; Shackleford, David M.; Barker, Helena; Ryan, Eileen; Scheurer, Christian; Tang, Yuanqing; Zhao, Qingjie; Zhou, Lin; White, Karen L.; Urwyler, Heinrich; Charman, William N.; Matile, Hugues; Wittlin, Sergio; Charman, Susan A.; Vennerstrom, Jonathan L.Journal of Medicinal Chemistry (2017), 60 (7), 2654-2668CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Building on insights gained from the discovery of the antimalarial ozonide arterolane (OZ277), we now describe the structure-activity relationship (SAR) of the antimalarial ozonide artefenomel (OZ439). Primary and secondary amino ozonides had higher metabolic stabilities than tertiary amino ozonides, consistent with their higher pKa and lower log D7.4 values. For primary amino ozonides, addn. of polar functional groups decreased in vivo antimalarial efficacy. For secondary amino ozonides, addnl. functional groups had variable effects on metabolic stability and efficacy, but the most effective members of this series also had the highest log D7.4 values. For tertiary amino ozonides, addn. of polar functional groups with H-bond donors increased metabolic stability but decreased in vivo antimalarial efficacy. Primary and tertiary amino ozonides with cycloalkyl and heterocycle substructures were superior to their acyclic counterparts. The high curative efficacy of these ozonides was most often assocd. with high and prolonged plasma exposure, but exposure on its own did not explain the presence or absence of either curative efficacy or in vivo toxicity.(e) Phyo, A. P.; Jittamala, P.; Nosten, F. N.; Pukrittayakamee, S.; Imwong, M.; White, N. J.; Duparc, S.; Macintyre, F.; Baker, M.; Möhrle, J. J. Antimalarial activity of artefenomel (OZ439), a novel synthetic antimalarial endoperoxide, in patients with Plasmodium falciparum and Plasmodium vivax malaria: an open-label phase 2 trial. Lancet Infect. Dis. 2016, 16, 61– 69, DOI: 10.1016/S1473-3099(15)00320-5[Crossref], [PubMed], [CAS], Google Scholar176ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhs1Wjs7vP&md5=368550e5ec73242c603c8abdc6a66f12Antimalarial activity of artefenomel (OZ439), a novel synthetic antimalarial endoperoxide, in patients with Plasmodium falciparum and Plasmodium vivax malaria: an open-label phase 2 trialPhyo, Aung Pyae; Jittamala, Podjanee; Nosten, Francois H.; Pukrittayakamee, Sasithon; Imwong, Mallika; White, Nicholas J.; Duparc, Stephan; MacIntyre, Fiona; Baker, Mark; Mohrle, Jorg J.Lancet Infectious Diseases (2016), 16 (1), 61-69CODEN: LIDABP; ISSN:1473-3099. (Elsevier Ltd.)Artefenomel (OZ439) is a novel synthetic trioxolane with improved pharmacokinetic properties compared with other antimalarial drugs with the artemisinin pharmacophore. Artefenomel has been generally well tolerated in volunteers at doses up to 1600 mg and is being developed as a partner drug in an antimalarial combination treatment. We investigated the efficacy, tolerability, and pharmacokinetics of artefenomel at different doses in patients with Plasmodium falciparum or Plasmodium vivax malaria. This phase 2a exploratory, open-label trial was done at the Hospital for Tropical Diseases, Bangkok, and the Shoklo Malaria Research Unit in Thailand. Adult patients with acute, uncomplicated P falciparum or P vivax malaria received artefenomel in a single oral dose (200 mg, 400 mg, 800 mg, or 1200 mg). The first cohort received 800 mg. Testing of a new dose of artefenomel in a patient cohort was decided on after safety and efficacy assessment of the preceding cohort. The primary endpoint was the natural log parasite redn. per 24 h. Definitive oral treatment was given at 36 h. This trial is registered with ClinicalTrials.gov, no. NCT01213966. Between Oct 24, 2010, and May 25, 2012, 82 patients were enrolled (20 in each of the 200 mg, 400 mg, and 800 mg cohorts, and 21 in the 1200 mg cohort). One patient withdrew consent (before the administration of artefenomel) but there were no further dropouts. The parasite redn. rates per 24 h ranged from 0·90 to 1·88 for P falciparum, and 2·09 to 2·53 for P vivax. All doses were equally effective in both P falciparum and P vivax malaria, with median parasite clearance half-lives of 4·1 h (range 1·3-6·7) to 5·6 h (2·0-8·5) for P falciparum and 2·3 h (1·2-3·9) to 3·2 h (0·9-15·0) for P vivax. Maximum plasma concns., dose-proportional to 800 mg, occurred at 4 h (median). The estd. elimination half-life was 46-62 h. No serious drug-related adverse effects were reported; other adverse effects were generally mild and reversible, with the highest no. in the 1200 mg cohort (17 [81%] patients with at least one adverse event). The most frequently reported adverse effect was an asymptomatic increase in plasma creatine phosphokinase concn. (200 mg, n=5; 400 mg, n=3; 800 mg, n=1; 1200 mg, n=3). Artefenomel is a new synthetic antimalarial peroxide with a good safety profile that clears parasitemia rapidly in both P falciparum and P vivax malaria. Its long half-life suggests a possible use in a single-dose treatment in combination with other drugs. Bill & Melinda Gates Foundation, Wellcome Trust, and UK Department for International Development.
- 177Opsenica, I.; Opsenica, D.; Smith, K. S.; Milhous, W. K.; Solaja, B. A. Chemical stability of the peroxide bond enables diversified synthesis of potent tetraoxane antimalarials. J. Med. Chem. 2008, 51, 2261– 2266, DOI: 10.1021/jm701417a[ACS Full Text], [CAS], Google Scholar177https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXjtFSksL8%253D&md5=1cbaada0a733461053126be47a63256fChemical stability of the peroxide bond enables diversified synthesis of potent tetraoxane antimalarialsOpsenica, Igor; Opsenica, Dejan; Smith, Kirsten S.; Milhous, Wilbur K.; Solaja, Bogdan A.Journal of Medicinal Chemistry (2008), 51 (7), 2261-2266CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Of 17 prepd. 1,2,4,5-tetraoxacyclohexanes stable to reductive and acidic conditions, 3 of them were more active than artemisinin against CQ and MFQ resistant strain TM91C235 and all compds. were more active in vitro against W2 than against D6 strain. In vivo, amines 10 and 11a cured all mice at higher doses with MCD ≤ 37.5 (mg/kg)/day. Triol 13 was exceptionally active against melanoma (LOX IMVI) and ovarian cancer (IGROV1), both with LC50 = 60 nM.
- 178(a) Ellis, G. L.; Amewu, R.; Sabbani, S.; Stocks, P. A.; Shone, A.; Stanford, D.; Gibbons, P.; Davies, J.; Vivas, L.; Charnaud, S.; Bongard, E.; Hall, C.; Rimmer, K.; Lozanom, S.; Jesús, M.; Gargallo, D.; Ward, S. A.; O’Neill, P. M. Two-step synthesis of achiral dispiro-1,2,4,5-tetraoxanes with outstanding antimalarial activity, low toxicity, and high-stability profiles. J. Med. Chem. 2008, 51, 2170– 2177, DOI: 10.1021/jm701435h[ACS Full Text.], [CAS], Google Scholar178ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXjtlOjsL4%253D&md5=3c4b69f56bbf84ca035f4fe62716073eTwo-Step Synthesis of Achiral Dispiro-1,2,4,5-tetraoxanes with Outstanding Antimalarial Activity, Low Toxicity, and High-Stability ProfilesEllis, Gemma L.; Amewu, Richard; Sabbani, Sunil; Stocks, Paul A.; Shone, Alison; Stanford, Deborah; Gibbons, Peter; Davies, Jill; Vivas, Livia; Charnaud, Sarah; Bongard, Emily; Hall, Charlotte; Rimmer, Karen; Lozanom, Sonia; Jesus, Maria; Gargallo, Domingo; Ward, Stephen A.; O'Neill, Paul M.Journal of Medicinal Chemistry (2008), 51 (7), 2170-2177CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Piperidinedispirotetraoxanes such as I (R = Et, cyclopropyl) are prepd. by a rapid, two-step method; the products have potent antimalarial activity both in vitro and in vivo. Sulfonylpiperidinones are prepd. by sulfonylation of 4-piperidinone hydrochloride with sulfonyl chlorides; oxidn. of the sulfonylpiperidinones with hydrogen peroxide in the presence of methyltrioxorhenium followed by cyclocondensation with either 2-adamantanone or cyclododecanone in the presence of fluoroboric acid in ether yields the title piperidinedispirotetraoxanes. The 1,2,4,5-tetraoxanes prepd. are more stable than similar 1,2,4-trioxolanes and are both more stable and more active as antimalarial agents than the corresponding 1,2,4-trioxanes. I (R = Et, cyclopropyl) showed no mutagenicity or cytotoxicity at the doses tested in a variety of cell lines. A fluorescent nitrobenzaoxadiazole-tagged tetraoxane is prepd. as a probe; laser scanning confocal microscopy of red blood cells dosed with the probe indicates that tagged mols. accumulate selectively only in parasite infected erythrocytes and that intraparasitic formation of adducts could be inhibited by co-incubation with the iron chelator desferrioxamine.(b) O’Neill, P. M.; Amewu, R. K.; Nixon, G. L.; El Garah, F. B.; Mungthin, M.; Chadwick, J.; Shone, A. E.; Vivas, L.; Lander, H.; Barton, V.; Muangnoicharoen, S.; Bray, P. G.; Davies, J.; Park, B. K.; Wittlin, S.; Brun, R.; Preschel, M.; Zhang, K.; Ward, S. A. Identification of a 1,2,4,5-tetraoxane antimalarial drug-development candidate (RKA182) with superior properties to the semisynthetic artemisinins. Angew. Chem., Int. Ed. 2010, 49, 5693– 5697, DOI: 10.1002/anie.201001026[Crossref], [CAS], Google Scholar.178bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXps1Cqtr4%253D&md5=fde585d889c5784302401ecead267127Identification of a 1,2,4,5-Tetraoxane Antimalarial Drug-Development Candidate (RKA 182) with Superior Properties to the Semisynthetic ArtemisininsO'Neill, Paul M.; Amewu, Richard K.; Nixon, Gemma L.; El Garah, Fatima Bousejra; Mungthin, Mathirut; Chadwick, James; Shone, Alison E.; Vivas, Livia; Lander, Hollie; Barton, Victoria; Muangnoicharoen, Sant; Bray, Patrick G.; Davies, Jill; Park, B. Kevin; Wittlin, Sergio; Brun, Reto; Preschel, Michael; Zhang, Kesheng; Ward, Stephen A.Angewandte Chemie, International Edition (2010), 49 (33), 5693-5697, S5693/1-S5693/10CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)We have identified the first water-sol. 1,2,4,5-tetraoxane drug candidate [I, RKA 182 (ditosylate)] that has outstanding antimalarial activity, stability, low toxicity and ADME properties (absorption, distribution, metab., and excretion) that overcome most of the problems encountered previously with the synthetic and semisynthetic antimalarial endoperoxide drugs that have progressed into preclin. development. This work firmly establishes the potential of the tetraoxane pharmacophore to provide the next generation of synthetic drugs for deployment in the control and eradication of malaria as a component of combination chemotherapy. The industrial synthesis of I comprises only four steps.(c) Marti, F.; Chadwick, J.; Amewu, R. K.; Burrell-Saward, H.; Srivastava, A.; Ward, S. A.; Sharma, R.; Berry, N.; O’Neill, P. M. Second generation analogues of RKA182: synthetic tetraoxanes with outstanding in vitro and in vivo antimalarial activities. MedChemComm 2011, 2, 661– 665, DOI: 10.1039/c1md00102g[Crossref], [CAS], Google Scholar.178chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXotl2gt7Y%253D&md5=f88d1f64a7f22a070d05c32f4b75fd08Second generation analogues of RKA182: synthetic tetraoxanes with outstanding in vitro and in vivo antimalarial activitiesMarti, Francesc; Chadwick, James; Amewu, Richard K.; Burrell-Saward, Hollie; Srivastava, Abhishek; Ward, Stephen A.; Sharma, Raman; Berry, Neil; O'Neill, Paul M.MedChemComm (2011), 2 (7), 661-665CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)A series of polar dispiro-1,2,4,5-tetraoxanes have been designed and synthesized by parallel synthesis. From this series, endoperoxides with activity as low as 0.2 nM have been obtained and representatives of this group have excellent oral activities in the P. berghei ANKA mouse model of malaria.(d) O’Neill, P. M.; Amewu, R. K.; Charman, S. A.; Sabbani, S.; Gnadig, N. F.; Straimer, J.; Fidock, D. A.; Shore, E. R.; Roberts, N. L.; Wong, M. H.; Hong, W. D.; Pidathala, C.; Riley, C.; Murphy, B.; Aljayyoussi, G.; Gamo, F. J.; Sanz, L.; Rodrigues, J.; Cortes, C. C.; Herreros, E.; Angulo-Barturen, I.; Jimenez-Dıaz, M. B.; Bazaga, S. F.; Martınez-Martınez, M. S.; Campo, B.; Sharma, R.; Ryan, E.; Shackleford, D. M.; Campbell, S.; Smith, D. A.; Wirjanata, G.; Noviyanti, R.; Price, R. N.; Marfurt, J.; Palmer, M. J.; Copple, I. M.; Mercer, A. E.; Ruecker, A.; Delves, M. J.; Sinden, R. E.; Sieg, P.; Davies, J.; Rochford, R.; Kocken, C. H.; Zeeman, A.; Nixon, G. L.; Biagini, G. A.; Ward, S. A. A tetraoxane-based antimalarial drug candidate that overcomes PfK13-C580Y dependent artemisinin resistance. Nat. Commun. 2017, 8, 15159, DOI: 10.1038/ncomms15159[Crossref], [PubMed], [CAS], Google Scholar178dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXot12gsb8%253D&md5=652486b04d3bf715b07ccf76c6226db0A tetraoxane-based antimalarial drug candidate that overcomes PfK13-C580Y dependent artemisinin resistanceO'Neill, Paul M.; Amewu, Richard K.; Charman, Susan A.; Sabbani, Sunil; Gnadig, Nina F.; Straimer, Judith; Fidock, David A.; Shore, Emma R.; Roberts, Natalie L.; Wong, Michael H.-L.; Hong, W. David; Pidathala, Chandrakala; Riley, Chris; Murphy, Ben; Aljayyoussi, Ghaith; Gamo, Francisco Javier; Sanz, Laura; Rodrigues, Janneth; Cortes, Carolina Gonzalez; Herreros, Esperanza; Angulo-Barturen, Inigo; Jimenez-Diaz, Maria Belen; Bazaga, Santiago Ferrer; Martinez-Martinez, Maria Santos; Campo, Brice; Sharma, Raman; Ryan, Eileen; Shackleford, David M.; Campbell, Simon; Smith, Dennis A.; Wirjanata, Grennady; Noviyanti, Rintis; Price, Ric N.; Marfurt, Jutta; Palmer, Michael J.; Copple, Ian M.; Mercer, Amy E.; Ruecker, Andrea; Delves, Michael J.; Sinden, Robert E.; Siegl, Peter; Davies, Jill; Rochford, Rosemary; Kocken, Clemens H. M.; Zeeman, Anne-Marie; Nixon, Gemma L.; Biagini, Giancarlo A.; Ward, Stephen A.Nature Communications (2017), 8 (), 15159CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)K13 gene mutations are a primary marker of artemisinin resistance in Plasmodium falciparum malaria that threatens the long-term clin. utility of artemisinin-based combination therapies, the cornerstone of modern day malaria treatment. Here we describe a multinational drug discovery program that has delivered a synthetic tetraoxane-based mol., E209, which meets key requirements of the Medicines for Malaria Venture drug candidate profiles. E209 has potent nanomolar inhibitory activity against multiple strains of P. falciparum and P. vivax in vitro, is efficacious against P. falciparum in in vivo rodent models, produces parasite redn. ratios equiv. to dihydroartemisinin and has pharmacokinetic and pharmacodynamic characteristics compatible with a single-dose cure. In vitro studies with transgenic parasites expressing variant forms of K13 show no cross-resistance with the C580Y mutation, the primary variant obsd. in Southeast Asia. E209 is a superior next generation endoperoxide with combined pharmacokinetic and pharmacodynamic features that overcome the liabilities of artemisinin derivs.
- 179(a) Counter, F. T.; Ensminger, P. W.; Preston, D. A.; Wu, C. Y.; Greene, J. M.; Felty-Duckworth, A. M.; Paschal, J. W.; Kirst, H. A. Synthesis and antimicrobial evaluation of dirithromycin (AS-E 13. LY237216), a new macrolide antibiotic derived from erythromycin. Antimicrob. Agents Chemother. 1991, 35, 1116– 1126, DOI: 10.1128/AAC.35.6.1116[Crossref], [PubMed], [CAS], Google Scholar.179ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXks1Cisrk%253D&md5=e544a289268426d9ba07565d1e63e97eSynthesis and antimicrobial evaluation of dirithromycin (ASE 136; LY237216), a new macrolide antibiotic derived from erythromycinCounter, Fred T.; Ensminger, Paul W.; Preston, David A.; Wu, Chyun Yeh E.; Greene, James M.; Felty-Duckworth, Anna M.; Paschal, Jonathan W.; Kirst, Herbert A.Antimicrobial Agents and Chemotherapy (1991), 35 (6), 1116-26CODEN: AMACCQ; ISSN:0066-4804.Dirithromycin (I) is a 9-N-11-O-oxazine deriv. which is formed by condensation of 9(S)-erythromycylamine with 2-(2-methoxyethoxy)acetaldehyde. I is hydrolyzed, either under acidic conditions or in vivo, to its major active metabolite, 9(S)-erythromycylamine. The antimicrobial spectrum of I is similar to that of erythromycin; both antibiotics are active against gram-pos. bacteria, Legionella spp., Helicobacter pylori, and Chlamydia trachomatis. Comparable results were obtained for each antibiotic in MIC and MBC detns. and in the potential development of resistance in vitro. The effects of human serum, bacterial growth media, test methodol., and inoculum size on MICs were similar for each antibiotic. In std. mouse protection studies, I was more efficaceous than erythromycin against exptl. infections after s.c. administration of antibiotic. These results were consistent with pharmacokinetic studies in rodents, which showed that I gave more persistent concns. of antibiotic in serum and tissues than were achieved with erythromycin. These studies indicate that I possesses antimicrobial activity comparable to that of erythromycin in vitro but is more active than erythromycin in vivo, which may be attributable to the persistence of antimicrobial activity in the tissue(s) of the test animals.(b) Mazzei, T.; Surrenti, C.; Novelli, A.; Biagini, M. R.; Fallani, S.; Cassetta, M. I.; Conti, S.; Surrenti, E. Pharmacokinetics of dirithromycin in patients with mild or moderate cirrhosis. Antimicrob. Agents Chemother. 1999, 43, 1556– 1559, DOI: 10.1128/AAC.43.7.1556[Crossref], [PubMed], [CAS], Google Scholar.179bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXktlCksrs%253D&md5=904d030556bc51a68a766b83954662fePharmacokinetics of dirithromycin in patients with mild or moderate cirrhosisMazzei, Teresita; Surrenti, Calogero; Novelli, Andrea; Biagini, Maria Rosa; Fallani, Stefania; Cassetta, Maria Iris; Conti, Silvia; Surrenti, ElisabettaAntimicrobial Agents and Chemotherapy (1999), 43 (7), 1556-1559CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)The pharmacokinetics of dirithromycin were detd. over a 72-h period following oral administration of a single 500-mg dose to healthy volunteers and to cirrhotic patients (patients with class A cirrhosis and patients with class B cirrhosis according to Pugh's & Child's classification). Drug levels in plasma and urine were detd. by microbiol. assay. The mean max. concns. of drug in serum obtained 3-4 h after administration were 0.29 mg/L in volunteers and 0.48 and 0.52 mg/L in patients with class A and class B cirrhosis, resp. The elimination half-life (t1/2β) was 23.3 h in healthy subjects and 35.2 h and 39.5 h in patients with class A and class B cirrhosis, resp. The mean area under the concn.-time curve (AUC) and t1/2β were higher in patients with class A and B cirrhosis than in healthy controls, while total and renal clearances were markedly reduced. The time required to reach the max. concn. of drug in serum and the vol. of distribution appeared to be similar in all groups, and the mean recovery in urine after 72 h ranged 3.7-5.7% of the dose, without significant differences among groups. These results demonstrate that some dirithromycin kinetic parameters are significantly different in cirrhotic patients in comparison to those in healthy volunteers. However, the increase in the t1/2β or AUC, which has also been obsd. with other semisynthetic macrolides (e.g., azithromycin), does not seem to be clin. relevant if one takes into account both the high therapeutic indexes of these antibiotics and the usually short duration of therapy. Therefore, on the limited basis of single-dose administration, no modifications of dirithromycin dosage seem to be required even for patients with class B liver cirrhosis.(c) Sides, G. D.; Cerimele, B. J.; Black, H. R.; Bosch, U.; DeSante, K. A. Pharmacokinetics of dirithromycin. J. Antimicrob. Chemother. 1993, 31, 65– 75, DOI: 10.1093/jac/31.suppl_C.65[Crossref], [PubMed], [CAS], Google Scholar.179chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3sXisVKrurs%253D&md5=47dbb7ffd00decdd57361433f0946012Pharmacokinetics of dirithromycinSides, Gregory D.; Cerimele, Benito J.; Black, Henry R.; Busch, Ulrich; DeSante, Karl A.Journal of Antimicrobial Chemotherapy (1993), 31 (Suppl. C), 65-75CODEN: JACHDX; ISSN:0305-7453.The human pharmacokinetics and clin. pharmacol. of dirithromycin were studied. Dirithromycin has unique pharmacokinetics which distinguish it from erythromycin. In man, following an oral 500-mg dose of dirithromycin, a mean peak plasma concn. (Cmax) of 0.48 mg/L (range 0.1-1.97) was obsd. at 4 h. The mean area under the plasma concn. vs. time curve (AUC0-24h) was 3.37 mg.h/L. No plasma accumulation was obsd. with multiple-dose administration. Dirithromycin may be taken without regard to meals, although food and H2-receptor antagonists may increase the systemic bioavailability in some patients. Based upon drug interaction studies performed with antipyrine and theophylline, dirithromycin showed less potential to interact with other drugs metabolized by the cytochrome P 450 system than did erythromycin. Plasma concns. and AUCs were low due to rapid movement of the drug from the vascular space to the extravascular compartment, as reflected by tissue concns., which exceeded plasma concns. 4 h after administration. Dirithromycin achieved relatively high tissue concns. (0.8-5.0 mg/kg) 4-24 h after administration. The extensive tissue penetration was reflected in a large mean apparent vol. of distribution of 800 L. Dirithromycin was rapidly converted by nonenzymic hydrolysis during absorption to erythromycylamine, which is microbiol. active. In a 14C-radiolabeled study, 60-90% of the administered dose was hydrolyzed to erythromycylamine within 35 min of infusion. After 1.5 h, conversion to erythromycylamine in serum was virtually complete. Plasma protein binding was 15-30%. Dirithromycin was characterized by a plasma elimination half-life of 44 h that permits once-daily administration. Total-body clearance was 226-1040 mL/min. The primary route of elimination of dirithromycin/erythromycylamine was fecal/hepatic. Following i.v. administration, approx. 17-25% of the radioactivity appeared in the urine and 62-81% appeared in the stools, indicating predominantly hepatic excretion. With oral administration 1.2-2.9% of the radioactivity appeared in the urine and 81-97% in the stools. The major part of urinary excretion occurred within the 1st 48 h postadministration; however, urinary excretion of radioactivity lasted >40 h. The abs. bioavailability calcd. from dose-cor. urinary excretion data was 10% (6-14%).(d) Shinkai, I.; Ohta, Y. Dirithromycin. Bioorg. Med. Chem. 1996, 4, 521– 522, DOI: 10.1016/0968-0896(96)00052-1[Crossref], [PubMed], [CAS], Google Scholar179dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XjtlWqs7s%253D&md5=e88125aa45c2cc268474eaa6d955996fDirithromycinShinkai, Ichiro; Ohta, YukariBioorganic & Medicinal Chemistry (1996), 4 (4), 521-522CODEN: BMECEP; ISSN:0968-0896. (Elsevier)The antibiotic action of dirithromycin, recently approved by the FDA, is discussed.
- 180(a) Khabibullina, N. F.; Tereshchenkov, A. G.; Komarova, E. S.; Syroegin, E. A.; Shiriaev, D. I.; Paleskava, A.; Kartsev, V. G.; Bogdanov, A. A.; Konevega, A. L.; Dontsova, O. A.; Sergiev, P. V.; Osterman, I. A.; Polikanov, Y. S. Structure of dirithromycin bound to the bacterial ribosome suggests new ways for rational improvement of macrolides. Antimicrob. Agents Chemother. 2019, 63, e02266 DOI: 10.1128/AAC.02266-18[Crossref], [PubMed], [CAS], Google Scholar.180ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhs1Smsr7J&md5=2398cfdb39103a5d78c2a833286fbbd6Structure of dirithromycin bound to the bacterial ribosome suggests new ways for rational improvement of macrolidesKhabibullina, Nelli F.; Tereshchenkov, Andrey G.; Komarova, Ekaterina S.; Syroegin, Egor A.; Shiriaev, Dmitrii I.; Paleskava, Alena; Kartsev, Victor G.; Bogdanov, Alexey A.; Konevega, Andrey L.; Dontsova, Olga A.; Sergiev, Petr V.; Osterman, Ilya A.; Polikanov, Yury S.Antimicrobial Agents and Chemotherapy (2019), 63 (6), e02266-18/1-e02266-18/8CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)Although macrolides are known as excellent antibacterials, their medical use has been significantly limited due to the spread of bacterial drug resistance. Therefore, it is necessary to develop new potent macrolides to combat the emergence of drug-resistant pathogens. One of the key steps in rational drug design is the identification of chem. groups that mediate binding of the drug to its target and their subsequent derivatization to strengthen drug-target interactions. In the case of macrolides, a few groups are known to be important for drug binding to the ribosome, such as desosamine. Search for new chem. moieties that improve the interactions of a macrolide with the 70S ribosome might be of crucial importance for the invention of new macrolides. For this purpose, here we studied a classic macrolide, dirithromycin, which has an extended (2-methoxyethoxy)-Me side chain attached to the C-9/C-11 atoms of the macrolactone ring that can account for strong binding of dirithromycin to the 70S ribosome. By solving the crystal structure of the 70S ribosome in complex with dirithromycin, we found that its side chain interacts with the wall of the nascent peptide exit tunnel in an idiosyncratic fashion: its side chain forms a lone pair-π stacking interaction with the arom. imidazole ring of the His69 residue in ribosomal protein uL4. To our knowledge, the ability of this side chain to form a contact in the macrolide binding pocket has not been reported previously and potentially can open new avenues for further exploration by medicinal chemists developing next-generation macrolide antibiotics active against resistant pathogens.(b) Pichkur, E. B.; Paleskava, A.; Tereshchenkov, A. G.; Kasatsky, P.; Komarova, E. S.; Shiriaev, D. I.; Bogdanov, A. A.; Dontsova, O. A.; Osterman, I. A.; Sergiev, P. V.; Polikanov, Y. S.; Myasnikov, A. G.; Konevega, A. L. Insights into the improved macrolide inhibitory activity from the high-resolution cryo-EM structure of dirithromycin bound to the E. coli 70S ribosome. RNA 2020, 26, 715– 723, DOI: 10.1261/rna.073817.119[Crossref], [PubMed], [CAS], Google Scholar180bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXit1KlsbjN&md5=9d3e3c6c0d8ef3835fdb7a27a0e9a0e9Insights into the improved macrolide inhibitory activity from the high-resolution cryo-EM structure of dirithromycin bound to the E. coli 70S ribosomePichkur, Evgeny B.; Paleskava, Alena; Tereshchenkov, Andrey G.; Kasatsky, Pavel; Komarova, Ekaterina S.; Shiriaev, Dmitrii I.; Bogdanov, Alexey A.; Dontsova, Olga A.; Osterman, Ilya A.; Sergiev, Petr V.; Polikanov, Yury S.; Myasnikov, Alexander G.; Konevega, Andrey L.RNA (2020), 26 (6), 715-723CODEN: RNARFU; ISSN:1355-8382. (Cold Spring Harbor Laboratory Press)Macrolides are one of the most successful and widely used classes of antibacterials, which kill or stop the growth of pathogenic bacteria by binding near the active site of the ribosome and interfering with protein synthesis. Dirithromycin is a deriv. of the prototype macrolide erythromycin with addnl. hydrophobic side chain. In our recent study, we have discovered that the side chain of dirithromycin forms lone pair-π stacking interaction with the arom. imidazole ring of the His69 residue in ribosomal protein uL4 of the Thermus thermophilus 70S ribosome. In the current work, we found that neither the presence of the side chain, nor the addnl. contact with the ribosome, improve the binding affinity of dirithromycin to the ribosome. Nevertheless, we found that dirithromycin is a more potent inhibitor of in vitro protein synthesis in comparison with its parent compd., erythromycin. Using high-resoln. cryo-electron microscopy, we detd. the structure of the dirithromycin bound to the translating Escherichia coli 70S ribosome, which suggests that the better inhibitory properties of the drug could be rationalized by the side chain of dirithromycin pointing into the lumen of the nascent peptide exit tunnel, where it can interfere with the normal passage of the growing polypeptide chain.
- 181(a) Wöhr, T.; Wahl, F.; Nefzi, A.; Rohwedder, B.; Sato, T.; Sun, X.; Mutter, M. Pseudo-prolines as a solubilizing, structure-disrupting protection technique in peptide synthesis. J. Am. Chem. Soc. 1996, 118, 9218– 9227, DOI: 10.1021/ja961509q .(b) Chaume, G.; Barbeau, O.; Lesot, P.; Brigaud, T. Synthesis of 2-trifluoromethyl-1,3-oxazolidines as hydrolytically stable pseudoprolines. J. Org. Chem. 2010, 75, 4135– 4145, DOI: 10.1021/jo100518t[ACS Full Text.], [CAS], Google Scholar181bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXmt12murg%253D&md5=ee99f09126da653cb834ba460fb4d8dbSynthesis of 2-trifluoromethyl-1,3-oxazolidines as hydrolytically stable pseudoprolinesChaume, Gregory; Barbeau, Olivier; Lesot, Philippe; Brigaud, ThierryJournal of Organic Chemistry (2010), 75 (12), 4135-4145CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)Trifluoromethyl group contg. oxazolidines (Fox) are conveniently synthesized by condensation of serine esters with trifluoroacetaldehyde hemiacetal or trifluoroacetone. These oxazolidines can undergo N-acylation and amidification reactions and are completely configurationally and hydrolytically stable. Therefore, they can be considered as highly valuable proline surrogates (Tfm-pseudoprolines).(c) Malquin, N.; Rahgoshay, K.; Lensen, N.; Chaume, G.; Miclet, E.; Brigaud, T. CF2H as a hydrogen bond donor group for the fine tuning of peptide bond geometry with difluoromethylated pseudoprolines. Chem. Commun. 2019, 55, 12487– 12490, DOI: 10.1039/C9CC05771D[Crossref], [PubMed], [CAS], Google Scholar.181chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvVersb7L&md5=5a3f14e2aec4ffe19922d4e23ac397e5CF2H as a hydrogen bond donor group for the fine tuning of peptide bond geometry with difluoromethylated pseudoprolinesMalquin, N.; Rahgoshay, K.; Lensen, N.; Chaume, G.; Miclet, E.; Brigaud, T.Chemical Communications (Cambridge, United Kingdom) (2019), 55 (83), 12487-12490CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)CF2H-Pseudoprolines obtained from difluoroacetaldehyde hemiacetal and serine are stable proline surrogates. The consequence of the incorporation of the CF2H group is an important decrease of the trans to cis amide bond isomerization energy and a remarkable stabilization of the cis conformer by an hydrogen bond.(d) Chaume, G.; Simon, J.; Caupéne, C.; Lensen, N.; Miclet, E.; Brigaud, T. Incorporation of CF3-pseudoprolines into peptides: a methodological study. J. Org. Chem. 2013, 78, 10144– 10153, DOI: 10.1021/jo401494q[ACS Full Text], [CAS], Google Scholar181dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVeksbbL&md5=21e72f67a8e6a6302632e3c062ef7dd7Incorporation of CF3-Pseudoprolines into Peptides: A Methodological StudyChaume, Gregory; Simon, Julien; Caupene, Caroline; Lensen, Nathalie; Miclet, Emeric; Brigaud, ThierryJournal of Organic Chemistry (2013), 78 (20), 10144-10153CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)The peptide coupling reactions allowing the incorporation of trifluoromethyl substituted oxazolidine-type pseudoprolines (CF3-ΨPro) into peptide chains have been studied. While std. protocols can be used for the peptide coupling reaction at the C-terminal position of the CF3-ΨPro, acid chloride activation has to be used for the peptide coupling reaction at the N-terminal position to overcome the decrease of nucleophilicity of the CF3-ΨPro. The authors demonstrate that the N-amidification of a diastereomeric mixt. of CF3-ΨPro using Fmoc-protected amino acid chloride without base gave the corresponding dipeptides as a single diastereomer (6 examples). The ratio of the cis and trans amide bond conformers was detd. by NMR study, highlighting the role of the Xaa side chains in the control of the peptide backbone conformation. Finally a tripeptide bearing a central CF3-ΨPro has been successfully synthesized.
- 182(a) Coburn, C. A.; Meinke, P. T.; Chang, W.; Fandozzi, C. M.; Graham, D. J.; Hu, B.; Huang, Q.; Kargman, S.; Kozlowski, J.; Liu, R.; McCauley, J. A.; Nomeir, A. A.; Soll, R. M.; Vacca, J. P.; Wang, D.; Wu, H.; Zhong, B.; Olsen, D. B.; Ludmerer, S. W. Discovery of MK-8742: an HCV NS5A inhibitor with broad genotype activity. ChemMedChem 2013, 8, 1930– 1940, DOI: 10.1002/cmdc.201300343[Crossref], [PubMed], [CAS], Google Scholar.182ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhs1SkurzN&md5=2f2b3ed2281c43e39b24d4197b9f57eeDiscovery of MK-8742: An HCV NS5A inhibitor with broad genotype activityCoburn, Craig A.; Meinke, Peter T.; Chang, Wei; Fandozzi, Christine M.; Graham, Donald J.; Hu, Bin; Huang, Qian; Kargman, Stacia; Kozlowski, Joseph; Liu, Rong; McCauley, John A.; Nomeir, Amin A.; Soll, Richard M.; Vacca, Joseph P.; Wang, Dahai; Wu, Hao; Zhong, Bin; Olsen, David B.; Ludmerer, Steven W.ChemMedChem (2013), 8 (12), 1930-1940CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)The NS5A protein plays a crit. role in the replication of HCV and has been the focus of numerous research efforts over the past few years. NS5A inhibitors have shown impressive in vitro potency profiles in HCV replicon assays, making them attractive components for inclusion in all oral combination regimens. Early work in the NS5A arena led to the discovery of our first clin. candidate, MK-4882 [2-((S)-pyrrolidin-2-yl)-5-(2-(4-(5-((S)-pyrrolidin-2-yl)-1H-imidazol-2-yl)phenyl)benzofuran-5-yl)-1H-imidazole]. While preclin. proof-of-concept studies in HCV-infected chimpanzees harboring chronic genotype 1 infections resulted in significant decreases in viral load after both single- and multiple-dose treatments, viral breakthrough proved to be a concern, thus necessitating the development of compds. with increased potency against a no. of genotypes and NS5A resistance mutations. Modification of the MK-4882 core scaffold by introduction of a cyclic constraint afforded a series of tetracyclic inhibitors, which showed improved virol. profiles. Herein we describe the research efforts that led to the discovery of MK-8742, a tetracyclic indole-based NS5A inhibitor, which is currently in phase 2b clin. trials as part of an all-oral, interferon-free regimen for the treatment of HCV infection.(b) Yu, W.; Tong, L.; Hu, B.; Zhong, B.; Hao, J.; Ji, T.; Zan, S.; Coburn, C. A.; Selyutin, O.; Chen, L.; Rokosz, L.; Agrawal, S.; Liu, R.; Curry, S.; McMonagle, P.; Ingravallo, P.; Asante-Appiah, E.; Chen, S.; Kozlowski, J. A. Discovery of chromane containing hepatitis C virus (HCV) NS5A inhibitors with improved potency against resistance-associated variants. J. Med. Chem. 2016, 59, 10228– 10243, DOI: 10.1021/acs.jmedchem.6b01234[ACS Full Text.], [CAS], Google Scholar182bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslGhu7zO&md5=6d6fa084bd50859fe090e42c545bc789Discovery of Chromane Containing Hepatitis C Virus (HCV) NS5A Inhibitors with Improved Potency against Resistance-Associated VariantsYu, Wensheng; Tong, Ling; Hu, Bin; Zhong, Bin; Hao, Jinglai; Ji, Tao; Zan, Shuai; Coburn, Craig A.; Selyutin, Oleg; Chen, Lei; Rokosz, Laura; Agrawal, Sony; Liu, Rong; Curry, Stephanie; McMonagle, Patricia; Ingravallo, Paul; Asante-Appiah, Ernest; Chen, Shiying; Kozlowski, Joseph A.Journal of Medicinal Chemistry (2016), 59 (22), 10228-10243CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The discovery of potent and pan-genotypic HCV NS5A inhibitors faces many challenges including the significant diversity among genotypes, substantial potency shift conferred on some key resistance-assocd. variants, inconsistent SARs between different genotypes and mutants, and the lacking of models of inhibitor/protein complexes for rational inhibitor design. As part of ongoing efforts on HCV NS5A inhibition at Merck, the authors now describe the discovery of a novel series of chromane contg. NS5A inhibitors. SAR studies around the "Z" group of the tetracyclic indole scaffold explored fused bicyclic rings as alternates to the Ph group of elbasvir (1, MK-8742) and identified novel chromane and 2,3-dihydrobenzofuran derivs. as "Z" group replacements offered good potency across all genotypes. This effort, incorporating the C-1 fluoro substitution at the tetracyclic indole core, led to the discovery of a new series of NS5A inhibitors with significantly improved potency against resistance-assocd. variants, such as GT2b, GT1a Y93H, and GT1a L31V. Compd. 14 (di-Me ((2S,2'S)-((2S,2'S)-((6-(Chroman-7-yl)-1-fluoro-6H-benzo[5,6][1,3]oxazino[3,4-a]indole-3,10-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobu-tane-1,2-diyl))dicarbamate) also showed reasonable PK exposures in preclin. species (rat and dog).(c) Tong, L.; Yu, W.; Chen, L.; Selyutin, O.; Dwyer, M. P.; Nair, A. G.; Mazzola, R.; Kim, J.; Sha, D.; Yin, J.; Ruck, R. T.; Davies, R. W.; Hu, B.; Zhong, B.; Hao, J.; Ji, T.; Zan, S.; Liu, R.; Agrawal, S.; Xia, E.; Curry, S.; McMonagle, P.; Bystol, K.; Lahser, F.; Carr, D.; Rokosz, L.; Ingravallo, P.; Chen, S.; Feng, K.; Cartwright, M.; Asante-Appiah, E.; Kozlowski, J. A. Discovery of ruzasvir (MK-8408): a potent, pan-genotype HCV NS5A inhibitor with optimized activity against common resistance-associated polymorphisms. J. Med. Chem. 2017, 60, 290– 306, DOI: 10.1021/acs.jmedchem.6b01310[ACS Full Text.], [CAS], Google Scholar182chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhslygt7jN&md5=6224e41b940abfb96cda518ecebf3e0fDiscovery of Ruzasvir (MK-8408): A Potent, Pan-Genotype HCV NS5A Inhibitor with Optimized Activity against Common Resistance-Associated PolymorphismsTong, Ling; Yu, Wensheng; Chen, Lei; Selyutin, Oleg; Dwyer, Michael P.; Nair, Anilkumar G.; Mazzola, Robert; Kim, Jae-Hun; Sha, Deyou; Yin, Jingjun; Ruck, Rebecca T.; Davies, Ian W.; Hu, Bin; Zhong, Bin; Hao, Jinglai; Ji, Tao; Zan, Shuai; Liu, Rong; Agrawal, Sony; Xia, Ellen; Curry, Stephanie; McMonagle, Patricia; Bystol, Karin; Lahser, Frederick; Carr, Donna; Rokosz, Laura; Ingravallo, Paul; Chen, Shiying; Feng, Kung-I.; Cartwright, Mark; Asante-Appiah, Ernest; Kozlowski, Joseph A.Journal of Medicinal Chemistry (2017), 60 (1), 290-306CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The authors describe the research that led to the discovery of compd. 40 (ruzasvir, MK-8408), a pan-genotypic HCV nonstructural protein 5A (NS5A) inhibitor with a "flat" GT1 mutant profile. This NS5A inhibitor contains a unique tetracyclic indole core, while maintaining the imidazole-proline-valine Moc motifs of the authors' previous NS5A inhibitors. Compd. 40 is currently in early clin. trials and is under evaluation as part of an all-oral DAA regimen for the treatment of chronic HCV infection.(d) Yu, W.; Tong, L.; Selyutin, O.; Chen, L.; Hu, B.; Zhong, B.; Hao, J.; Ji, T.; Zan, S.; Yin, J.; Ruck, R. T.; Curry, S.; McMonagle, P.; Agrawal, S.; Rokosz, L.; Carr, D.; Ingravallo, P.; Bystol, K.; Lahser, F.; Liu, R.; Chen, S.; Feng, K.; Cartwright, M.; Asante-Appiah, E.; Kozlowski, J. A. Discovery of MK-6169, a potent pan-genotype hepatitis C virus NS5A inhibitor with optimized activity against common resistance-associated substitutions. J. Med. Chem. 2018, 61, 3984– 4003, DOI: 10.1021/acs.jmedchem.7b01927[ACS Full Text.], [CAS], Google Scholar182dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXotVahtro%253D&md5=9f8fb68f245d3e189136badeff91571eDiscovery of MK-6169, a Potent Pan-Genotype Hepatitis C Virus NS5A Inhibitor with Optimized Activity against Common Resistance-Associated SubstitutionsYu, Wensheng; Tong, Ling; Selyutin, Oleg; Chen, Lei; Hu, Bin; Zhong, Bin; Hao, Jinglai; Ji, Tao; Zan, Shuai; Yin, Jingjun; Ruck, Rebecca T.; Curry, Stephanie; McMonagle, Patricia; Agrawal, Sony; Rokosz, Laura; Carr, Donna; Ingravallo, Paul; Bystol, Karin; Lahser, Frederick; Liu, Rong; Chen, Shiying; Feng, Kung-I.; Cartwright, Mark; Asante-Appiah, Ernest; Kozlowski, Joseph A.Journal of Medicinal Chemistry (2018), 61 (9), 3984-4003CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)We describe the discovery of MK-6169 (I), a potent and pan-genotype hepatitis C virus NS5A inhibitor with optimized activity against common resistance-assocd. substitutions. SAR studies around the combination of changes to both the valine and aminal carbon region of elbasvir led to the discovery of a series of compds. with substantially improved potency against common resistance-assocd. substitutions in the major genotypes, as well as good pharmacokinetics in both rat and dog. Through further optimization of key leads from this effort, MK-6169 (I) was discovered as a preclin. candidate for further development.(e) https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208261Orig1s000PharmR.pdf (accessed April 2, 2021.)
- 183(a) Reading, C.; Cole, M. Clavulanic acid: a β-lactamase-inhibiting β-lactam from Streptomyces clavuligerus. Antimicrob. Agents Chemother. 1977, 11, 852– 857, DOI: 10.1128/AAC.11.5.852[Crossref], [PubMed], [CAS], Google Scholar.183ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE2sXks1GjtLw%253D&md5=f418af59b52360c0ffe187922c0ef99dClavulanic acid: a beta-lactamase-inhibiting beta-lactam from Streptomyces clavuligerusReading, C.; Cole, M.Antimicrobial Agents and Chemotherapy (1977), 11 (5), 852-7CODEN: AMACCQ; ISSN:0066-4804.A novel β-lactamase inhibitor has been isolated from S. clavuligerus ATCC 27064 and given the name clavulanic acid (I). Conditions for the cultivation of the organism and detection and isolation of I are described. This compd. resembles the nucleus of a penicillin but differs in having no acylamino side chain, having O instead of S, and contg. a β-hydroxyethylidine substituent in the oxazolidine ring. I is a potent inhibitor of many β-lactamases, including those found in Escherichia coli (plasmid mediated), Klebsiella aerogenes, Proteus mirabilis, and Staphylococcus aureus, the inhibition being of a progressive type. The cephalosporinase type of β-lactamase found in Pseudomonas aeruginosa and Enterobacter cloacae P99 and the chromosomally mediated β-lactamase of E. coli are less well inhibited. The min. inhibitory concns. of ampicillin and cephaloridine against β-lactamase-producing, penicillin-resistant strains of S. aureus, K. aerogenes, P. mirabilis, and E. coli are considerably reduced by the addn. of low concns. of I.(b) Buynak, J. D. Understanding the longevity of the β-lactam antibiotics and of antibiotic/β-lactamase inhibitor combinations. Biochem. Pharmacol. 2006, 71, 930– 940, DOI: 10.1016/j.bcp.2005.11.012[Crossref], [PubMed], [CAS], Google Scholar183bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XitVKjurc%253D&md5=003ecb0fa5b73a67115a6f081394fac7Understanding the longevity of the β-lactam antibiotics and of antibiotic/β-lactamase inhibitor combinationsBuynak, John D.Biochemical Pharmacology (2006), 71 (7), 930-940CODEN: BCPCA6; ISSN:0006-2952. (Elsevier B.V.)A review. Microbial resistance necessitates the search for new targets and new antibiotics. However, it is likely that resistance problems will eventually threaten these new products and it may, therefore, be instructive to review the successful employment of β-lactam antibiotic/β-lactamase inhibitor combinations to combat penicillin resistance. These combination drugs have proven successful for more than two decades, with inhibitor resistance still being relatively rare. The β-lactamase inhibitors are mechanism-based irreversible inactivators. The ability of the inhibitors to avoid resistance may be due to the structural similarities between the substrate and inhibitor.
- 184(a) Brown, R. P.; Aplin, R. T.; Schofield, C. J. Inhibition of TEM-2 β-lactamase from Escherichia coli by clavulanic acid: observation of intermediates by electrospray ionization mass spectrometry. Biochemistry 1996, 35, 12421– 12432, DOI: 10.1021/bi961044g[ACS Full Text.], [CAS], Google Scholar184ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XltlCqs7c%253D&md5=eda160601cb775ff61d402f6d34c6050Inhibition of TEM-2 β-lactamase from Escherichia coli by clavulanic acid: observation of intermediates by electrospray ionization mass spectrometryBrown, Roland P. A.; Aplin, Robin T.; Schofield, Christopher J.Biochemistry (1996), 35 (38), 12421-12432CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)Clavulanic acid, the therapeutically important inhibitor of β-lactamases contg. a nucleophilic serine residue at their active sites, inhibits Escherichia coli TEM-2 β-lactamase via a complex mechanism. Electrospray ionization mass spectrometry (ESIMS) studies revealed that a min. of four different modified proteins are formed upon incubation of clavulanate with the TEM-2 enzyme. These exhibit mass increments relative to the unmodified TEM-2 β-lactamase of 52, 70, 88, and 155 Da. Time course studies implied that no long-lived forms of clavulanate-inhibited TEM-2 β-lactamase retain the carbons of the oxazolidine ring of clavulanate. The absence of a 199-Da increment to unmodified TEM-2 suggests rapid decarboxylation of clavulanate upon binding to the enzyme. Proteolytic digestions of purified forms of clavulanate inhibited TEM-2 β-lactamase followed by analyses using HPLC coupled to ESIMS (HPLC-ESIMS) and chem. sequencing were used to provide positional information on the modifications to the enzyme. Increments of 70 and 80-Da increments were shown to be located in a peptide contg. Ser 70. A further 70-Da mass increment, assigned as a β-linked acrylate, was localized to a peptide contg. Ser 130. A mechanistic scheme for the reaction of clavulanate with TEM-2 β-lactamase is proposed in which acylation at Ser 70 and subsequent decarboxylation is followed either by crosslinking with Ser 130 to form a vinyl ether or by reformation of unmodified enzyme via a Ser 70 linked (hydrated) aldehyde. Purified crosslinked vinyl ether was obsd. to slowly convert under acidic conditions to a Ser 70 linked (hydrated) aldehyde with concomitant conversion of Ser 130 to a dehydroalanine residue.(b) Imtiaz, U.; Billings, E.; Knox, J. R.; Manavathu, E. K.; Lerner, S. A.; Mobashery, S. Inactivation of class A β-lactamases by clavulanic acid: the role of arginine-244 in a proposed nonconcerted sequence of events. J. Am. Chem. Soc. 1993, 115, 4435– 4442, DOI: 10.1021/ja00064a003[ACS Full Text], [CAS], Google Scholar184bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3sXisFSnsr0%253D&md5=672b2943e1d3e8490a0aa1bafe41e305Inactivation of class A β-lactamases by clavulanic acid: the role of arginine-244 in a proposed nonconcerted sequence of eventsImtiaz, Uzma; Billings, Eric; Knox, James R.; Manavathu, Elias K.; Lerner, Stephen A.; Mobashery, ShahriarJournal of the American Chemical Society (1993), 115 (11), 4435-42CODEN: JACSAT; ISSN:0002-7863.From the refined 2-Å crystal structure of β-lactamase (I) of Bacillus licheniformis 749/C, which shares a high sequence homol. with TEM-1 I, energy-minimized models for active site binding of the precatalytic (Michaelis) complex with the clin. utilized inactivator, clavulanic acid (II), for the acyl-enzyme intermediate, and for the ultimate acylated acyclic species that leads to inactivation of class A I by II were generated. On the basis of these models, the details of the chem. of I inactivation by II were reassessed. A nonconcerted mechanism for the inactivation chem. of class A I by II was proposed. These models revealed that the Arg-244 side-chain and the Val-216 carbonyl anchor a structurally conserved water mol., W673, which serves as the most likely source of a crit. proton in a stepwise sequence of events. Disruption of this electrostatic anchor for W673 by mutational replacement of Arg-244 with Ser in TEM I would account for the resulting obsd. severe impairment of the efficiency of inactivation of the mutant enzyme by II. The kinetic impact of the Arg-244-Ser mutation on interaction with II was reflected by resistance to ampicillin plus II of a strain of Escherichia coli bearing the mutant enzyme. Mol. dynamics computations on the acylated acyclic intermediate, the putative inactivating species, indicated that irreversible inactivation of I may not occur as a consequence of a transimination reaction, in contrast to previous suggestions. The most likely scenario for irreversible inactivation involves the capture of the β-OH group of conserved Ser-130 by the iminium moiety of the acylated acyclic intermediate, followed by deprotonation at C6 of II. The deprotonation is likely to be carried out by the conserved Glu-166 via the intervening crystallog. water W712. Deprotonation prior to nucleophile capture is proposed as the mechanism of generation of the so-called transiently inhibited enamine species. For wild-type TEM-1 I, both irreversible inactivation and the formation of the transiently inhibited species proceed with comparable rates. In addn., a new function for the Ser-130 in the formation of the acyl-enzyme intermediate with both II and typical I substrates is proposed. It is suggested that the β-OH group of Ser-130 stabilizes the transition state for the expulsion of the incipient amine from the high-energy tetrahedral species by H-bonding to the oxazolidine amine in the course of Ser-70 acylation.
- 185Haginaka, J.; Nakagawa, T.; Uno, T. Stability of clavulanic acid in aqueous solutions. Chem. Pharm. Bull. 1981, 29, 3334– 3341, DOI: 10.1248/cpb.29.3334[Crossref], [CAS], Google Scholar185https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL38XlslKlsA%253D%253D&md5=f9ab8243de4406223ee81ddf32d996feStability of clavulanic acid in aqueous solutionsHaginaka, Jun; Nakagawa, Terumichi; Uno, ToyozoChemical & Pharmaceutical Bulletin (1981), 29 (11), 3334-41CODEN: CPBTAL; ISSN:0009-2363.The stability of clavulanic acid (I) [58001-44-8] in aq. solns. was investigated over a pH range of 3.15 to 10.10 at 35° and at an ionic strength of 0.5. The changes in the concn. of intact I in buffer solns. were detd. by reversed phase HPLC with UV-detection using a mobile phase contg. Bu4NBr. The obsd. degrdn. rates at various pH's followed pseudo-first-order kinetics, and were significantly affected by catalysis due to buffer salts. The catalytic rate consts. were estd. at 3 different concns. of buffer systems. The pH vs. rate profiles obtained from non-buffer-catalyzed rate consts., kpH, revealed that the degrdn. in alk. solns. proceeded, as a whole, about 10 times faster than in acidic media, and max. stability was attained at pH 6.39. The Arrhenius activation energies at pH 3.94, 6.67, and 8.74 were est. as 19.0, 14.7, and 18.3 kcal/mol., resp.
- 186(a) Adam, D.; de Visser, I.; Koeppe, P. Pharmacokinetics of amoxicillin and clavulanic acid administered alone and in combination. Antimicrob. Agents Chemother. 1982, 22, 353– 357, DOI: 10.1128/AAC.22.3.353[Crossref], [PubMed], [CAS], Google Scholar.186ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL3sXmsFShtA%253D%253D&md5=2914359f7c115fa0bfd9a2afb6ac1c28Pharmacokinetics of amoxicillin and clavulanic acid administered alone and in combinationAdam, Dieter; De Visser, Iris; Koeppe, PeterAntimicrobial Agents and Chemotherapy (1982), 22 (3), 353-7CODEN: AMACCQ; ISSN:0066-4804.The pharmacokinetics of amoxicillin (I) [26787-78-0] and clavulanic acid (II) [58001-44-8], administered alone and as a I-II mixt. [74469-00-4], were studied in normal human volunteers. Each ingested 500 mg of I or 125 mg of II or the I-II mixt. in randomized sequence. The results indicate that most of the parameters tested for either substance are essentially independent of the presence of the other one.(b) Navarro, A. S. New formulations of amoxicillin/clavulanic acid. Clin. Pharmacokinet. 2005, 44, 1097– 1115, DOI: 10.2165/00003088-200544110-00001 .(c) De Velde, F.; De Winter, B. C. M.; Koch, B. C. P.; Van Gelder, T.; Mouton, J. W. and the COMBACTE-NET consortium. Highly variable absorption of clavulanic acid during the day: a population pharmacokinetic analysis. J. Antimicrob. Chemother. 2018, 73, 469– 476, DOI: 10.1093/jac/dkx376[Crossref], [PubMed], [CAS], Google Scholar186chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitlCjsr3F&md5=ad77302f46166a7d8f9763b44b018ea8Highly variable absorption of clavulanic acid during the day:a population pharmacokinetic analysisDe Velde, Femke; De Winter, Brenda C. M.; Koch, Birgit C. P.; Van Gelder, Teun; Mouton, Johan W.Journal of Antimicrobial Chemotherapy (2018), 73 (2), 469-476CODEN: JACHDX; ISSN:1460-2091. (Oxford University Press)Objectives: To calc. the clavulanic acid exposure of oral amoxicillin/clavulanic acid dosing regimens, to investigate variability using a population pharmacokinetic model and to explore target attainment using Monte Carlo simulations. Methods: Two groups of healthy male volunteers received amoxicillin/clavulanic acid tablets at the start of a std. meal on two sep. days 1 wk apart. One group (n=14) received 875/125mg q12h and 500/125mg q8h and the other group (n=15) received 500/125mg q12h and 250/125mg q8h. In total, 1479 blood samples were collected until 8-12 h after administration. Concns. were analyzed using non-compartmental (WinNonLin) and population pharmacokinetic (NONMEM) methods. Results: Median Cmax and AUC0-8 were 2.21mg/L (0.21-4.35) and 4.99 mg·h/L (0.44-8.31), resp. In 40/58 daily concn.-time profiles, Cmax and AUC0-8 of the morning dose were higher than with later doses.The final population model included a lag time (0.447 h), first-order absorption (3.99 h-1 at 8:00 h, between subject variability 52.8%, between-occasion variability 48.5%), one distribution compartment (33.0 L, between subject variability 23.9%) and first-order elimination (24.6 L/h, between-subject variability 26.7%). Bioavailability (fixed at 1 at 8:00 h, between-occasion variability 28.2%) and absorption rate decreased over the day. For 97.5% of the simulated population after 125mg q12h or q8h, %fT>Ct at 0.5mg/L was 8.33% (q12h) and 15.2% (q8h), %fT>Ct at 1mg/Lwas 0%(q12h+q8h), and fAUC0-24 was 3.61 (q12h) and 5.56 (q8h) mg·h/L. Conclusions: Clavulanic acid absorption in healthy volunteers is highly variable. Bioavailability and absorption rate decrease over the day. The model developed here may serve to suggest clavulanic acid dosing regimens to optimize efficacy and prevent underdosing.
- 187(a) Krishnan, B. R.; James, K. D.; Polowy, K.; Bryant, B.; Vaidya, A.; Smith, S.; Laudeman, C. P. CD101, a novel echinocandin with exceptional stability properties and enhanced aqueous solubility. J. Antibiot. 2017, 70, 130– 135, DOI: 10.1038/ja.2016.89[Crossref], [PubMed], [CAS], Google Scholar.187ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhs1ait78%253D&md5=538cd97a5dcc6307960567417d8b5ab2CD101, a novel echinocandin with exceptional stability properties and enhanced aqueous solubilityKrishnan, B. Radha; James, Kenneth D.; Polowy, Karen; Bryant, B. J.; Vaidya, Anu; Smith, Steve; Laudeman, Christopher P.Journal of Antibiotics (2017), 70 (2), 130-135CODEN: JANTAJ; ISSN:0021-8820. (Nature Publishing Group)The echinocandins are an important class of antifungal agents. However, instability and, in some cases, lack of soly. have restricted their use to situations in which daily infusions are acceptable. CD101 is a novel echinocandin in development for topical and weekly i.v. administration that exhibits prolonged stability in plasma and aq. solns. up to 40°. After incubation for 44 h in rat, dog, monkey and human plasma at 37°, the percent of CD101 remaining (91%, 79%, 94% and 93%, resp.) was consistently greater than that of anidulafungin (7%, 15%, 14% and 7%, resp.). Similarly, after incubation in phosphate-buffered saline at 37°, the CD101 remaining (96%) was greater than that of anidulafungin (42%). CD101 exhibited <2% degrdn. after long-term storage at 40° as a lyophilized powder (9 mo) and at room temp. in 5% dextrose (15 mo), 0.9% saline (12 mo) and sterile water (18 mo). Degrdn. was <7% at 40° in acetate and lactate buffers (6 to 9 mo at pH 4.5-5.5). The chem. stability and soly. of CD101 contribute to dosing, pharmacokinetic, formulation and safety advantages over other echinocandins and should expand utility beyond daily i.v. therapy.(b) Sofjan, A. K.; Mitchell, A.; Shah, D. N.; Nguyen, T.; Sim, M.; Trojcak, A.; Beyda, N. D.; Garey, K. W. Rezafungin (CD101), a next-generation echinocandin: A systematic literature review and assessment of possible place in therapy. J. Global Antimicrob. Resist. 2018, 14, 58– 64, DOI: 10.1016/j.jgar.2018.02.013[Crossref], [PubMed], [CAS], Google Scholar187bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1MrlvFSjsA%253D%253D&md5=34824f471858dbb7add390cfbb93c5cbRezafungin (CD101), a next-generation echinocandin: A systematic literature review and assessment of possible place in therapySofjan Amelia K; Mitchell Ardath; Shah Dhara N; Nguyen Tam; Sim Mui; Trojcak Ashley; Beyda Nicholas D; Garey Kevin WJournal of global antimicrobial resistance (2018), 14 (), 58-64 ISSN:.OBJECTIVES: Rezafungin (CD101) is a novel echinocandin currently under development. The purpose of this study was to perform a systematic literature review of published evidence on rezafungin and an antimicrobial stewardship audit of real-world use of echinocandins to determine areas of unmet medical needs and potential places in therapy for rezafungin. METHODS: The systematic literature review identified 8 peer-reviewed manuscripts and 19 separate abstracts. A stewardship audit was performed on hospitalised patients receiving echinocandins to better understand potential future areas of use for rezafungin. RESULTS: Rezafungin is a cyclic hexapeptide with a lipophilic tail derived from anidulafungin, with a choline moiety at the C5 ornithine position resulting in increased in vitro and in vivo stability compared with other echinocandins. Microbiological data showed similar susceptibility and resistance development between rezafungin and other echinocandins. Rezafungin has a long half-life (80h) and a favourable safety profile that allows for high doses (up to 400mg) given once weekly. A phase 2 study is ongoing. The antimicrobial stewardship audit of echinocandin identified several areas of possible use for rezafungin, including patients receiving daily echinocandins for >7 days, patients who remained in the hospital to complete a full course of daily echinocandin therapy, and patients who required an echinocandin scheduled via an infusion clinic after discharge. CONCLUSION: Rezafungin is a novel echinocandin currently in phase 2 studies, differentiated by a long half-life that allows once-weekly dosing and a safety profile that allows higher doses. Several potential areas of use for rezafungin were identified.
- 188Kofla, G.; Ruhnke, M. Pharmacology and metabolism of anidulafungin, caspofungin and micafungin in the treatment of invasive candidosis: review of the literature. Eur. J. Med.Res. 2011, 16, 159– 166, DOI: 10.1186/2047-783X-16-4-159[Crossref], [PubMed], [CAS], Google Scholar188https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXot1OhtLw%253D&md5=71507c21beeb35f67464739857c110e2Pharmacology and metabolism of anidulafungin, caspofungin and micafungin in the treatment of invasive candidosis - review of the literatureKofla, G.; Ruhnke, M.European Journal of Medical Research (2011), 16 (4), 159-166CODEN: EJMRFL; ISSN:0949-2321. (I. Holzapfel Verlag GmbH)A review. Echinocandins represent the newest class of antifungal agents. Currently, three echinocandins, anidulafungin, caspofungin and micafungin are licensed for clin. use in various indications. They act as inhibitors of β-(1,3)-glucan synthesis in the fungal cell wall and have a favorable pharmacol. profile. They have a broad spectrum of activity against all Candida species. Higher MIC's have been obsd. against C. parapsilosis and C. guilliermondii. Data from clin. trials for invasive Candida infections / candidemia suggest that the clin. outcome of patients treated with either drug may be very similar. A comparison has been done between caspofungin and micafungin but for anidulafungin a comparative trial with another echinocandin is still lacking. All three drugs are highly effective if not superior to treatment with either fluconazole or Amphotericin B, particularly in well-defined clin. settings such as invasive Candida infections, Candida oesophagitis and candidemia. Differences between the three echinocandins with regard to the route of metab., requirement for a loading dose, dose adjustment in patients with moderate to severe hepatic disease and different dosing schedules for different types of Candida infections have to be considered. Relevant drug-drug interactions of Caspofungin and Micafungin are minimal. Anidulafungin has no significant drug interactions at all. However, echinocandins are available only for i.v. use. All three agents have an excellent safety profile.
- 189(a) Johns, B. A.; Kawasuji, T.; Weatherhead, J. G.; Taishi, T.; Temelkoff, D. P.; Yoshida, H.; Akiyama, T.; Taoda, Y.; Murai, H.; Kiyama, R.; Fuji, M.; Tanimoto, N.; Jeffrey, J.; Foster, S. A.; Yoshinaga, T.; Seki, T.; Kobayashi, M.; Sato, A.; Johnson, M. N.; Garvey, E. P.; Fujiwara, T. Carbamoyl pyridone HIV-1 integrase inhibitors 3. A diastereomeric approach to chiral nonracemic tricyclic ring systems and the discovery of dolutegravir (S/GSK1349572) and (S/GSK1265744). J. Med. Chem. 2013, 56, 5901– 5916, DOI: 10.1021/jm400645w[ACS Full Text.], [CAS], Google Scholar189ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtVWhurfK&md5=c44c9e62870c2177b07cdd08d22ea600Carbamoyl Pyridone HIV-1 Integrase Inhibitors 3. A Diastereomeric Approach to Chiral Nonracemic Tricyclic Ring Systems and the Discovery of Dolutegravir (S/GSK1349572) and (S/GSK1265744)Johns, Brian A.; Kawasuji, Takashi; Weatherhead, Jason G.; Taishi, Teruhiko; Temelkoff, David P.; Yoshida, Hiroshi; Akiyama, Toshiyuki; Taoda, Yoshiyuki; Murai, Hitoshi; Kiyama, Ryuichi; Fuji, Masahiro; Tanimoto, Norihiko; Jeffrey, Jerry; Foster, Scott A.; Yoshinaga, Tomokazu; Seki, Takahiro; Kobayashi, Masanori; Sato, Akihiko; Johnson, Matthew N.; Garvey, Edward P.; Fujiwara, TamioJournal of Medicinal Chemistry (2013), 56 (14), 5901-5916CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)We report herein the discovery of the human immunodeficiency virus type-1 (HIV-1) integrase inhibitors dolutegravir (S/GSK1349572) (3, III) and S/GSK1265744 (4, IV). These drugs stem from a series of carbamoyl pyridone analogs designed using a two-metal chelation model of the integrase catalytic active site. Structure-activity studies evolved a tricyclic series of carbamoyl pyridines that demonstrated properties indicative of once-daily dosing and superior potency against resistant viral strains. An inherent hemiaminal ring fusion stereocenter within the tricyclic carbamoyl pyridone scaffold led to a crit. substrate controlled diastereoselective synthetic strategy whereby chiral information from small readily available amino alcs. was employed to control relative and abs. stereochem. of the final drug candidates. Modest to extremely high levels of stereochem. control were obsd. depending on ring size and position of the stereocenter. This approach resulted in the discovery of 3 and 4, which are currently in clin. development.(b) Kawasuji, T.; Johns, B. A.; Yoshida, H.; Weatherhead, J. G.; Akiyama, T.; Taishi, T.; Taoda, Y.; Mikamiyama-Iwata, M.; Murai, H.; Kiyama, R.; Fuji, M.; Tanimoto, N.; Yoshinaga, T.; Seki, T.; Kobayashi, M.; Sato, A.; Garvey, E. P.; Fujiwara, T. Carbamoyl pyridone HIV-1 integrase inhibitors. 2. Bi- and tricyclic derivatives result in superior antiviral and pharmacokinetic profiles. J. Med. Chem. 2013, 56, 1124– 1135, DOI: 10.1021/jm301550c[ACS Full Text.], [CAS], Google Scholar189bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXntVeltA%253D%253D&md5=4bfe919f8fdbbc84e346e3f01e084b70Carbamoyl Pyridone HIV-1 Integrase Inhibitors. 2. Bi- and Tricyclic Derivatives Result in Superior Antiviral and Pharmacokinetic ProfilesKawasuji, Takashi; Johns, Brian A.; Yoshida, Hiroshi; Weatherhead, Jason G.; Akiyama, Toshiyuki; Taishi, Teruhiko; Taoda, Yoshiyuki; Mikamiyama-Iwata, Minako; Murai, Hitoshi; Kiyama, Ryuichi; Fuji, Masahiro; Tanimoto, Norihiko; Yoshinaga, Tomokazu; Seki, Takahiro; Kobayashi, Masanori; Sato, Akihiko; Garvey, Edward P.; Fujiwara, TamioJournal of Medicinal Chemistry (2013), 56 (3), 1124-1135CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)This work is a continuation of our initial discovery of a potent monocyclic carbamoyl pyridone human immunodeficiency virus type-1 (HIV-1) integrase inhibitor that displayed favorable antiviral and pharmacokinetic properties. We report herein a series of bicyclic carbamoylpyridone (I; satd. and unsatd. bridge; R = e.g., alkoxyethyl) analogs to address conformational issues from our initial SAR studies. This modification of the core unit succeeded to deliver low nanomolar potency in std. antiviral assays. An addnl. hydroxyl substituent on the bicyclic scaffold provides remarkable improvement of antiviral efficacies against clin. relevant resistant viruses. These findings led to addnl. cyclic tethering of the naked hydroxyl group resulting in tricyclic carbamoyl pyridone inhibitors (II; Y = O, N; n = 0-2; R' = e.g., alkyl, Ac, methanesulfonyl) to address remaining issues and deliver potential clin. candidates. The tricyclic carbamoyl pyridone derivs. described herein served as the immediate leads in mols. to the next generation integrase inhibitor dolutegravir which is currently in late stage clin. evaluation.(c) Kawasuji, T.; Johns, B. A.; Yoshida, H.; Taishi, T.; Taoda, Y.; Murai, H.; Kiyama, R.; Fuji, M.; Yoshinaga, T.; Seki, T.; Kobayashi, M.; Sato, A.; Fujiwara, T. Carbamoyl pyridone HIV-1 integrase inhibitors. 1. Molecular design and establishment of an advanced two-metal binding pharmacophore. J. Med. Chem. 2012, 55, 8735– 8744, DOI: 10.1021/jm3010459[ACS Full Text], [CAS], Google Scholar189chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhtlags7zO&md5=fa751e3f5da1cede1a76cc26c7a15d3aCarbamoyl Pyridone HIV-1 Integrase Inhibitors. 1. Molecular Design and Establishment of an Advanced Two-Metal Binding PharmacophoreKawasuji, Takashi; Johns, Brian A.; Yoshida, Hiroshi; Taishi, Teruhiko; Taoda, Yoshiyuki; Murai, Hitoshi; Kiyama, Ryuichi; Fuji, Masahiro; Yoshinaga, Tomokazu; Seki, Takahiro; Kobayashi, Masanori; Sato, Akihiko; Fujiwara, TamioJournal of Medicinal Chemistry (2012), 55 (20), 8735-8744CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Our group has focused on expanding the scope of a two-metal binding pharmacophore concept to explore HIV-1 integrase inhibitors through medicinal chem. efforts to design novel scaffolds which allow for improvement of pharmacokinetic (PK) and resistance profiles. A novel chelating scaffold was rationally designed to effectively coordinate two magnesium cofactors and to extend an arom. group into an optimal hydrophobic pharmacophore space. The new chemotype, consisting of a carbamoyl pyridone core unit, shows high inhibitory potency in both enzymic and antiviral assay formats with low nM IC50 and encouraging potency shift effects in the presence of relevant serum proteins. The new inhibitor design displayed a remarkable PK profile suggestive of once daily dosing without the need for a PK booster as demonstrated by robust drug concns. at 24 h after oral dosing in rats, dogs, and cynomolgus monkeys.
- 190(a) Tsiang, M.; Jones, G. S.; Goldsmith, J.; Mulato, A.; Hansen, D.; Kan, E.; Tsai, L.; Bam, R. A.; Stepan, G.; Stray, K. M.; Niedziela-Majka, A.; Yant, S. R.; Yu, H.; Kukolj, G.; Cihlar, T.; Lazerwith, S. E.; White, K. L.; Jin, H. Antiviral activity of bictegravir (GS-9883), a novel potent HIV-1 integrase strand transfer inhibitor with an improved resistance profile. Antimicrob. Agents Chemother. 2016, 60, 7086– 7097, DOI: 10.1128/AAC.01474-16[Crossref], [PubMed], [CAS], Google Scholar.190ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXitlWjt78%253D&md5=87a180a313ffaa8b03201b06a8c875ffAntiviral activity of bictegravir (GS-9883), a novel potent HIV-1 integrase strand transfer inhibitor with an improved resistance profileTsiang, Manuel; Jones, Gregg S.; Goldsmith, Joshua; Mulato, Andrew; Hansen, Derek; Kan, Elaine; Tsai, Luong; Bam, Rujuta A.; Stepan, George; Stray, Kirsten M.; Niedziela-Majka, Anita; Yant, Stephen R.; Yu, Helen; Kukolj, George; Cihlar, Tomas; Lazerwith, Scott E.; White, Kirsten L.; Jin, HaolunAntimicrobial Agents and Chemotherapy (2016), 60 (12), 7086-7097CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)Bictegravir (BIC; GS-9883), a novel, potent, once-daily, unboosted inhibitor of HIV-1 integrase (IN), specifically targets IN strand transfer activity (50% inhibitory concn. [IC50] of 7.5 ± 0.3 nM) and HIV-1 integration in cells. BIC exhibits potent and selective in vitro antiretroviral activity in both T-cell lines and primary human T lymphocytes, with 50% effective concns. ranging from 1.5 to 2.4 nM and selectivity indexes up to 8,700 relative to cytotoxicity. BIC exhibits synergistic in vitro antiviral effects in pairwise combinations with tenofovir alafenamide, emtricitabine, or darunavir and maintains potent antiviral activity against HIV-1 variants resistant to other classes of antiretrovirals. BIC displayed an in vitro resistance profile that was markedly improved compared to the integrase strand transfer inhibitors (INSTIs) raltegravir (RAL) and elvitegravir (EVG), and comparable to that of dolutegravir (DTG), against nine INSTI-resistant site-directed HIV-1 mutants. BIC displayed statistically improved antiviral activity relative to EVG, RAL, and DTG against a panel of 47 patient-derived HIV-1 isolates with highlevel INSTI resistance; 13 of 47 tested isolates exhibited >2-fold lower resistance to BIC than DTG. In dose-escalation expts. conducted in vitro, BIC and DTG exhibited higher barriers to resistance than EVG, selecting for HIV-1 variants with reduced phenotypic susceptibility at days 71, 87, and 20, resp. A recombinant virus with the BIC-selected M50I/R263K dual mutations in IN exhibited only 2.8-fold reduced susceptibility to BIC compared to wild-type virus. All BIC-selected variants exhibited low to intermediate levels of cross-resistance to RAL, DTG, and EVG (<8-fold) but remained susceptible to other classes of antiretrovirals. A high barrier to in vitro resistance emergence for both BIC and DTG was also obsd. in viral breakthrough studies in the presence of const. clin. relevant drug concns. The overall virol. profile of BIC supports its ongoing clin. investigation in combination with other antiretroviral agents for both treatment-naive and -experienced HIV-infected patients.(b) Lazerwith, S. E.; Cai, R.; Chen, X.; Chin, G.; Desai, M. C.; Eng, S.; Jacques, R.; Ji, M.; Jones, G.; Martin, H.; McMahon, C.; Mish, M.; Morganelli, P.; Mwangi, J.; Pyun, H.; Schmitz, U.; Stepan, G.; Szwarcberg, J.; Tang, J.; Tsiang, M.; Wang, J.; Wang, K.; White, K.; Wiser, L.; Zack, J.; Jin, H. Discovery of bictegravir (GS-9883), a novel, unboosted, once-daily HIV-1 integrase strand transfer inhibitor (INSTI) with improved pharmacokinetics and in vitro resistance profile. ASM Microbe: Boston, MA, 2016.
- 191Deeks, E. D. Bictegravir/emtricitabine/tenofovir alafenamide: a review in HIV-1 infection. Drugs 2018, 78, 1817– 1828, DOI: 10.1007/s40265-018-1010-7[Crossref], [PubMed], [CAS], Google Scholar191https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXit1GgtbbK&md5=ffec7739b3a4dda20f945a8dd3539422Bictegravir/Emtricitabine/Tenofovir Alafenamide: A Review in HIV-1 InfectionDeeks, Emma D.Drugs (2018), 78 (17), 1817-1828CODEN: DRUGAY; ISSN:0012-6667. (Springer International Publishing AG)Bictegravir is a new integrase strand transfer inhibitor (INSTI) with a high genetic barrier to the development of HIV-1 resistance. The drug is co-formulated with the nucleos(t)ide reverse transcriptase inhibitors emtricitabine and tenofovir alafenamide (AF) in a single-tablet regimen (STR) for the once-daily treatment of HIV-1 infection in adults (bictegravir/emtricitabine/tenofovir AF; Biktarvy). In phase 3 trials, bictegravir/emtricitabine/tenofovir AF was noninferior to dolutegravir-based therapy (dolutegravir/abacavir/lamivudine or dolutegravir plus emtricitabine/tenofovir AF) in establishing virol. suppression in treatment-naive adults through 96 wk' treatment and, similarly, was noninferior to ongoing dolutegravir/abacavir/lamivudine or boosted elvitegravir- or protease inhibitor (PI)-based therapy in preventing virol. rebound over 48 wk in treatment-experienced patients. No resistance emerged to any of the antiretrovirals in the STR. Bictegravir/emtricitabine/tenofovir AF is generally well tolerated, requires no prior HLA-B*5701 testing (making it more suitable for 'rapid start' treatment), fulfils the antiretroviral regimen requirement for patients with hepatitis B virus (HBV) co-infection (i.e. contains tenofovir AF and emtricitabine, both of which are active against HBV) and can be used in renally impaired patients with creatinine clearance (CRCL) ≥ 30 mL/min. Thus, although cost-effectiveness analyses would be beneficial, current data indicate that bictegravir/emtricitabine/tenofovir AF is a convenient initial and subsequent treatment option for adults with HIV-1 infection, including those co-infected with HBV, and provides the first non-pharmacol. boosted, INSTI-based, triple-combination STR suitable for patients with CRCL 30-50 mL/min.
- 192(a) Wu, Y.-J.; Guernon, J.; Rajamani, R.; Toyn, J. H.; Ahlijanian, M. K.; Albright, C. F.; Muckelbauer, J.; Chang, C.; Camac, D.; Macor, J. E.; Thompson, L. A. Discovery of furo[2,3-d][1,3]thiazinamines as β-amyloid cleaving enzyme-1 (BACE1) inhibitors. Bioorg. Med. Chem. Lett. 2016, 26, 5729– 5731, DOI: 10.1016/j.bmcl.2016.10.055[Crossref], [PubMed], [CAS], Google Scholar.192ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhsl2itr7F&md5=95eacab8d71d6a4ab35e1b436029b829Discovery of furo[2,3-d][1,3]thiazinamines as beta amyloid cleaving enzyme-1 (BACE1) inhibitorsWu, Yong-Jin; Guernon, Jason; Rajamani, Ramkumar; Toyn, Jeremy H.; Ahlijanian, Michael K.; Albright, Charles F.; Muckelbauer, Jodi; Chang, ChiehYing; Camac, Dan; Macor, John E.; Thompson, Lorin A.Bioorganic & Medicinal Chemistry Letters (2016), 26 (23), 5729-5731CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)This Letter describes the synthesis and structure-activity relationships of a series of furo[2,3-d][1,3]thiazinamine BACE1 inhibitors. The co-crystal structure of a representative thiazinamine I bound with the BACE1 active site displayed a binding mode driven by interactions with the catalytic aspartate dyad and engagement of the biaryl amide toward the S1 and S3 pockets. This work indicates that furo[2,3-d]thiazine can serve as a viable bioisostere of the known furo[3,4-d]thiazine.(b) Wu, Y.-J.; Guernon, J.; Park, H.; Thompson, L. A. Expedient synthesis of fluoro[2,3-d[1,3]thiazinamines and pyrano-[2,3-d][1,3]thiazinamines from enones and thiourea. J. Org. Chem. 2016, 81, 3386– 3390, DOI: 10.1021/acs.joc.5b02705[ACS Full Text], [CAS], Google Scholar192bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XksFGrsro%253D&md5=4cc318a4bd852be9795f0f41e464c1dfExpedient Synthesis of Furo[2,3-d][1,3]thiazinamines and Pyrano[2,3-d][1,3]thiazinamines from Enones and ThioureaWu, Yong-Jin; Guernon, Jason; Park, Hyunsoo; Thompson, Lorin A.Journal of Organic Chemistry (2016), 81 (8), 3386-3390CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)Michael addn. of thiourea to enones with subsequent intramol. aminal ether formation provided easy access to furo[2,3-d]thiazinamines and pyrano[2,3-d][1,3]thiazin-2-amines. These amines served as versatile intermediates to a variety of beta-amyloid cleaving enzyme-1 (BACE1) inhibitors.
- 193Futamura, A.; Suzuki, R.; Tamura, Y.; Kawamoto, H.; Ohmichi, M.; Hino, N.; Tokumaru, Y.; Kirinuki, S.; Hiyoshi, T.; Aoki, T.; Kambe, D.; Nozawa, D. Discovery of ORN0829, a potent dual orexin 1/2 receptor antagonist for the treatment of insomnia. Bioorg. Med. Chem. 2020, 28, 115489, DOI: 10.1016/j.bmc.2020.115489[Crossref], [PubMed], [CAS], Google Scholar193https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtVOmu73J&md5=a48f3baab0761535af73ffa790b9835cDiscovery of ORN0829, a potent dual orexin 1/2 receptor antagonist for the treatment of insomniaFutamura, Aya; Suzuki, Ryo; Tamura, Yunoshin; Kawamoto, Hiroshi; Ohmichi, Mari; Hino, Noriko; Tokumaru, Yuichi; Kirinuki, Sora; Hiyoshi, Tetsuaki; Aoki, Takeshi; Kambe, Daiji; Nozawa, DaiBioorganic & Medicinal Chemistry (2020), 28 (13), 115489CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)Here, the authors present the design, synthesis, and SAR of dual orexin I and II receptor antagonists, which were optimized by balancing the antagonistic activity for orexin receptors and lipophilicity. Based on the prototype compd. I, ring construction and the insertion of an addnl. heteroatom into the resulting ring led to the discovery of orexin I and II receptor antagonists, which were 3-benzoyl-1,3-oxazinane derivs. Within these derivs., III enabled a high dual orexin receptor antagonistic activity and a low lipophilicity. Compd. III exhibited potent sleep-promoting effects at a po dose of 1 mg/kg in a rat polysomnogram study, and optimal PK properties with a rapid Tmax and short half-lives in rats and dogs were obsd., indicating a predicted human half-life of 0.9-2.0 h. Thus, III(ORN0829; study code name, TS-142) was selected as a viable candidate and is currently in clin. development for the treatment of insomnia.
- 194(a) Miller, T. W.; Goegelman, R. T.; Weston, R. G.; Putter, I.; Wolf, F. J. Cephamycins, a new family of β-lactam antibiotics. II. Isolation and chemical characterization. Antimicrob. Agents Chemother. 1972, 2, 132– 135, DOI: 10.1128/AAC.2.3.132[Crossref], [PubMed], [CAS], Google Scholar.194ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE3sXjvFOgtg%253D%253D&md5=5be8b99ea02792cdff1649ae81936011Cephamycins, a new family of β-lactam antibiotics. II. Isolation and chemical characterizationMiller, T. W.; Goegelman, R. T.; Weston, R. G.; Putter, I.; Wolf, F. J.Antimicrobial Agents and Chemotherapy (1972), 2 (3), 132-5CODEN: AMACCQ; ISSN:0066-4804.Fermentation broths from cultures of various microorganisms were used for the sepn. of cephamycins A, B, and C. The broths were acidified and absorbed onto a column of Amberlite XAD-2. After elution with 60% aq. methanol, the eluate was concd., adjusted to pH 3.5 with NH4OH, and absorbed onto a column of Amberlite IRZ-68 (Cl-). This was eluted with 1M NaNO3 + 0.1M NaOAc at pH 7.5. The eluate was adjusted to pH 3 and absorbed onto Amberlite XAD-2, eluted with 25% aq. acetone, and concd. under reduced pressure. The material was then sepd. by DEAE-Sephadex A-25 resin using const. buffer elution with 0.5M NH4Br + 0.05M AcOH. The sepd. cephamycins A and B were desalted using Amberlite XAD-2, and lyophilized. Cephamycin C was prepd. by a different process in which the fermentation broth was passed through a column of Dowex 1-X2 (Cl-) and eluted with 5% aq. NaCl soln. The high activity fractions were acidified to pH 2 with HCl, adsorbed onto Dowex 50-X2 (H+), and eluted with 2% aq. pyridine. The eluate was neutralized with NaOH soln. and concd. under reduced pressure. This was absorbed onto a column of Dowex 1-X2 (Cl-) equilibrated with 0.1M pyridine-HCl buffer at pH 5, and the column was developed with the same buffer. The high activity fractions were adjusted to pH 8 and dried. This material was desalted by chromatog. on Biogel-P2. The 3 cephamycins were analyzed to det. their empirical formulas, mol. wts., uv spectra, amino acid analysis, and CD. Cephamycin C was identical to antibiotic 4 reported by Nagarajan, R., et al. (1971), but cephamycins A and B appeared to be new compds.(b) Stapley, E. O.; Birnbaum, J.; Miller, A. K.; Wallick, H.; Hendlin, D.; Woodruff, H. B. Cefoxitin and cephamycins: microbiological studies. Clin. Infect. Dis. 1979, 1, 73– 87, DOI: 10.1093/clinids/1.1.73
- 195Brites, L. M.; Oliveira, L. M.; Barboza, M. Kinetic study on cephamycin C degradation. Appl. Biochem. Appl. Biochem. Biotechnol. 2013, 171, 2121– 2128, DOI: 10.1007/s12010-013-0502-x[Crossref], [PubMed], [CAS], Google Scholar195https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVCitrvO&md5=c00dc6d568997c8967e68fcee4350953Kinetic Study on Cephamycin C DegradationBrites, Luciana M.; Oliveira, Liliane M.; Barboza, MarleiApplied Biochemistry and Biotechnology (2013), 171 (8), 2121-2128CODEN: ABIBDL; ISSN:0273-2289. (Springer)Cephamycin C (CepC) is a β-lactam antibiotic that belongs to the cephalosporin class of drugs. This compd. stands out from other cephalosporins for its greater resistance to β-lactamases, which are enzymes produced by pathogenic microorganisms that present a major mechanism of bacterial resistance to β-lactam antibiotics. Cephamycin C is produced by the bacterium Streptomyces clavuligerus. Knowledge about the stability of the compd. under different values of pH is important for the development of the process of prodn., extn., and purifn. aimed at obtaining higher yields. Therefore, the stability of cephamycin C under different pH levels (2.2, 6.0, 7.0, 7.6, and 8.7) at 20 °C was evaluated in this study. Ultrafiltered broth from batch fermns. of S. clavuligerus was used in the trials. The results indicated that cephamycin C is a more stable compd. than other β-lactam compds. such as penicillin and clavulanic acid. A higher degrdn. rate was obsd. at very acidic or basic pH levels, while this rate was lower at quasi-neutral pH levels. After 100 h of trial, the initial CepC showed 46 % degrdn. at pH 2.2, 71 % degrdn. at pH 8.7, and varied from 15 to 20 % at quasi-neutral pH levels.
- 196(a) Hagmann, W. K.; Thompson, K. R.; Shah, S. K.; Finke, P. E.; Ashe, B. M.; Weston, H.; Maycock, A. L.; Doherty, J. B. The effect of N-acyl substituents on the stability of monocyclic β-lactam inhibitors of human leukocyte elastase. Bioorg. Med. Chem. Lett. 1992, 2, 681– 684, DOI: 10.1016/S0960-894X(00)80390-X[Crossref], [CAS], Google Scholar.196ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3sXkt1ensLk%253D&md5=ce657004b4e19cdb99073afa3c197242The effect of N-acyl substituents on the stability of monocyclic β-lactam inhibitors of human leukocyte elastaseHagmann, William K.; Thompson, Kevan R.; Shah, Shrenik K.; Finke, Paul E.; Ashe, Bonnie M.; Weston, Hazel; Maycock, Alan L.; Doherty, James B.Bioorganic & Medicinal Chemistry Letters (1992), 2 (7), 681-4CODEN: BMCLE8; ISSN:0960-894X.Substituted monocyclic β-lactams have recently been reported as inhibitors of human leukocyte elastase (HLE). Simple N-acetyl-2-azetidinone lead structures were found to undergo N-deacylation as well as β-lactam ring opening. The development of the N-carbamoyl-2-azetidinone nucleus was crucial to the stability of these compds. for effective oral bioavailability.(b) Finke, P. E.; Shah, S. K.; Fletcher, D. S.; Ashe, B. M.; Brause, K. A.; Chandler, G. O.; Dellea, P. S.; Hand, K. M.; Maycock, A. L. Orally active β-lactam inhibitors of human leukocyte elastase. 3. Stereospecific synthesis and structure-activity relationships for 3,3-dialkylazetidin-2-ones. J. Med. Chem. 1995, 38, 2449– 2462, DOI: 10.1021/jm00013a021[ACS Full Text.], [CAS], Google Scholar196bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXmtVyhsbY%253D&md5=a413402d09b5abfa9fad9b7301fe8a02Orally Active β-Lactam Inhibitors of Human Leukocyte Elastase. 3. Stereospecific Synthesis and Structure-Activity Relationships for 3,3-Dialkylazetidin-2-onesFinke, Paul E.; Shah, Shrenik K.; Fletcher, Daniel S.; Ashe, Bonnie M.; Brause, Karen A.; Chandler, Gilbert O.; Dellea, Pam S.; Hand, Karen M.; Maycock, Alan L.; et al.Journal of Medicinal Chemistry (1995), 38 (13), 2449-62CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The stereospecific synthesis of several 4-[(4-carboxyphenyl)oxy]-3,3-dialkyl-1-[[(1-phenylalkyl)amino]carbonyl]azetidin-2-ones I [R1 = R2 = H, Rβ = H, Me, Et, n-Pr, etc., Rα = Et, Me, n-Pr, allyl, RβRα = (CH2)4; R1 = Me, H, Et, n-Pr, R2 = H, Me, Et, Rβ = Me, n-Pr, Rα = Et] is described in which the C-3 alkyl groups were varied from Me to Bu as well as allyl, benzyl and methoxymethyl. The structure-activity relations for these compds. are discussed in terms of the hydrolytic stability of the β-lactam ring, their in vitro inhibitory potency for human leukocyte elastase (HLE), and their in vivo oral efficacy in an HLE-mediated hamster lung hemorrhage assay. Further alkyl substitution on the benzylic urea moiety, esp. in the R configuration, afforded enhanced HLE inhibition and in vivo efficacy. The stereochem. assignments for (3R,4S)-4-[(4-carboxyphenyl)oxy]-3-ethyl-3-methyl-1-[[((R)-1-phenylpropyl)amino]carbonyl]azetidin-2-one (kobs/[I] = 91 000 M-1 s-1) were confirmed with an X-ray structure detn., which was also utilized to develop an HLE inhibition model.(c) Doherty, J. B.; Shah, S. K.; Finke, P. E.; Dorn, C. P.; Hagmann, W. K.; Hale, J. J.; Kissinger, A. L.; Thompson, K. R.; Brause, K.; Chandler, G. O. Chemical, biochemical, pharmacokinetic, and biological properties of L-680,833: a potent, orally active monocyclic β-lactam inhibitor of human polymorphonuclear leukocyte elastase. Proc. Natl. Acad. Sci. U. S. A. 1993, 90, 8727– 8731, DOI: 10.1073/pnas.90.18.8727[Crossref], [PubMed], [CAS], Google Scholar.196chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXjslA%253D&md5=17ff24f09bc6b8cfa04b07dd2cb0b4b3Chemical, biochemical, pharmacokinetic, and biological properties of L-680,833: A potent, orally active monocyclic β-lactam inhibitor of human polymorphonuclear leukocyte elastaseDoherty, James B.; Shah, Shrenik K.; Finke, Paul E.; Dorn, Conrad P., Jr.; Hagmann, William K.; Hale, Jeffrey J.; Kissinger, Amy L.; Thompson, Kevan R.; Brause, Karen; et al.Proceedings of the National Academy of Sciences of the United States of America (1993), 90 (18), 8727-31CODEN: PNASA6; ISSN:0027-8424.A series of potent and highly selective time-dependent monocyclic β-lactam inhibitors of human polymorphonuclear leukocyte elastase (PMNE, EC 3.4.21.37) is described. The intrinsic potency of these compds., as exemplified by L-680,833 (kinactivation/Ki of 622,000 M-1-s-1), is reflected at the cellular level where it inhibits generation of the specific N-terminal cleavage product Aα-(1-21) from the Aα chain of fibrinogen by enzyme released from isolated polymorphonuclear leukocytes stimulated with fMet-Leu-Phe with an IC50 of 0.06 μM. The inhibitory activity of L-680,833 is also apparent in whole blood stimulated with A23187, where it inhibits formation of Aα-(1-21) and PMNE-α1-proteinase inhibitor complex formation with IC50 values of 9 μM. Pharmacokinetic studies indicate that after oral dosing L-680,833 is bioavailable in rats and rhesus monkeys. This oral bioavailability is reflected by the inhibition (i) of tissue damage elicited in hamster lungs by intratracheal instillation of human PMNE and (ii) enzyme released from human PMN stimulated after their transfer into the pleural cavity of mice. The properties of L-680,833 allow it to effectively supplement the activity of natural inhibitors of PMNE in vivo, suggesting that this type of low-mol.-wt. synthetic inhibitor could have therapeutic value in diseases where PMNE damages tissue.(d) Vincent, S. H.; Painter, S. K.; Luffer-Atlas, D.; Karanam, B. V.; McGowan, E.; Cioffe, C.; Doss, G.; Chiu, S. Orally active inhibitors of human leukocyte elastase. II. Disposition of L-694,458 in rats and rhesus monkeys. Drug Metab. Dispos. 1997, 25, 932– 939[PubMed], [CAS], Google Scholar196dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXlsVGmsr0%253D&md5=8238bfaaa41c61c88424fff290dfec31Orally active inhibitors of human leukocyte elastase. II. Disposition of L-694,458 in rats and rhesus monkeysVincent, Styliani H.; Painter, Susan K.; Luffer-Atlas, Debra; Karanam, Bindhu V.; Mcgowan, E.; Cloffe, Chris; Doss, George; Chlu, Shuet-Hing L.Drug Metabolism and Disposition (1997), 25 (8), 932-939CODEN: DMDSAI; ISSN:0090-9556. (Williams & Wilkins)The disposition of L-694,458, a potent monocyclic β-lactam inhibitor of human leukocyte elastase, was studied in male Sprague-Dawley rats and rhesus monkeys. After i.v. dosing, L-694,458 exhibited similar pharmacokinetic parameters in rats and rhesus monkeys. The mean values for its plasma clearance, terminal half-life, and vol. of distribution at steady state were 27 mL/min/kg, 1.8 h, and 4.0 L/kg in rats and 34 mL/min/kg, 2.3 h, and 5 L/kg in rhesus monkeys. The bioavailability of a 10 mg/kg oral dose was higher in rats (65%) than in rhesus monkeys (39%). In both species, concns. of L-694,458 in plasma increased more than proportionally when the oral dose was increased from 10 mg/kg to 40 mg/kg. In monkeys a protracted plasma concn.-time profile was obsd. at 40 mg/kg, characterized by a delayed Tmax (8-24 h) and a long terminal half-life (6 h). [3H]L-694,458 was well absorbed after oral dosing to rats at 10 mg/kg, as indicated by the high recovery of radioactivity in bile (83%) and urine (6%) of bile duct-cannulated rats. Only ∼5% or less of the radioactivity in bile, urine, and feces was a result of intact L-694,458, indicating that the compd. was being eliminated by metab., followed by excretion of the metabolites in feces, via bile. Demethylation of the methylenedioxyphenyl group resulting in the catechol was the primary metabolic pathway in human and rhesus monkey liver microsomes. In rat liver microsomes, the major metabolite was the N-oxide of the methyl-substituted piperazine nitrogen. In rats dosed i.v. and orally with [3H]L-694,458, concns. of radioactivity were highest in the lung (the primary target tissue), adrenals, and liver. L-694,458 was unstable in rat blood and plasma, degrading via a pathway believed to be catalyzed by B-esterases and to involve cleavage of the β-lactam ring and loss of the methylpiperazine phenoxy group. In vitro studies indicated that in human liver, L-694,458 was metabolized by CYP3A and CYP2C isoenzymes, and in both monkey and human liver microsomes the compd. acted as an inhibitor of testosterone 6β-hydroxylation.
- 197Halas, C. J. Eszopiclone. Am. J. Health-Syst. Pharm. 2006, 63, 41– 48, DOI: 10.2146/ajhp050357[Crossref], [PubMed], [CAS], Google Scholar197https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XntVCmuw%253D%253D&md5=9845c47e5baec4f9a8d75b0e49cbba1fEszopicloneHalas, Cynthia J.American Journal of Health-System Pharmacy (2006), 63 (1), 41-48CODEN: AHSPEK; ISSN:1079-2082. (American Society of Health-System Pharmacists)A review. Purpose. The pharmacol., pharmacokinetics, indications, clin. efficacy, adverse effects, drug interactions, dosing, and administration of eszopiclone are discussed. Summary. The pharmacol. of eszopiclone is not well understood. Eszopiclone is the S-isomer of racemic zopiclone. The relative bioavailability of oral racemic zopiclone is about 80%. Eszopiclone is rapidly absorbed after oral administration, with peak serum concns. ranging from 1 to 1.3 h. The efficacy of eszopiclone has been evaluated in healthy adults, including elderly patients, for the treatment of transient and chronic insomnia. Compared with placebo, eszopiclone has been shown to considerably reduce sleep induction and improve sleep maintenance, duration, quality, and depth, as well as next-day functioning. The most common adverse effects reported are unpleasant taste, headache, and dry mouth. Dosing should be individualized, and the lowest ED should be used to minimize the risk of adverse events. The recommended starting dosage for nonelderly patients is 2 mg immediately before bedtime, with adjustment to 3 mg if clin. indicated. Dosage adjustment is necessary in patients with severe hepatic disease and in those receiving concomitant potent cytochrome P 450 isoenzyme 3A4 inhibitors. No dosage adjustment is required for patients with renal dysfunction. The cost of eszopiclone is $3.70 per tablet for all dosage strengths (1-, 2-, and 3-mg tablets). Conclusion. Its favorable adverse-effect profile and approved labeling for the treatment of chronic insomnia makes eszopiclone a viable alternative for insomnia treatment. Published data are limited, however, and more clin. trials, including comparator studies, are needed to further evaluate the use of this drug.
- 198(a) Shelton, J.; Lu, X.; Hollenbaugh, J. A.; Cho, J. H.; Amblard, F.; Schinazi, R. F. Metabolism, biochemical actions, and chemical synthesis of anticancer nucleosides, nucleotides, and base analogues. Chem. Rev. 2016, 116, 14379– 14455, DOI: 10.1021/acs.chemrev.6b00209[ACS Full Text.], [CAS], Google Scholar198ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhvFWgtL3J&md5=84cbe9e13e6bdaff88a9d49caea2f99aMetabolism, Biochemical Actions, and Chemical Synthesis of Anticancer Nucleosides, Nucleotides, and Base AnalogsShelton, Jadd; Lu, Xiao; Hollenbaugh, Joseph A.; Cho, Jong Hyun; Amblard, Franck; Schinazi, Raymond F.Chemical Reviews (Washington, DC, United States) (2016), 116 (23), 14379-14455CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. Nucleoside, nucleotide, and base analogs have been in the clinic for decades to treat both viral pathogens and neoplasms. More than 20% of patients on anticancer chemotherapy have been treated with one or more of these analogs. This review focuses on the chem. synthesis and biol. of anticancer nucleoside, nucleotide, and base analogs that are FDA-approved and in clin. development since 2000. The authors highlight the cellular biol. and clin. biol. of analogs, drug resistance mechanisms, and compd. specificity towards different cancer types. Furthermore, the authors explore analog syntheses as well as improved and scale-up syntheses. The authors conclude with a discussion on what might lie ahead for medicinal chemists, biologists, and physicians as they try to improve analog efficacy through prodrug strategies and drug combinations.(b) Seley-Radtke, K.; Yates, M. K. The evolution of nucleoside analogue antivirals: a review for chemists and non-chemists. Part I: Early structural modifications to the nucleoside scaffold. Antiviral Res. 2018, 154, 66– 86, DOI: 10.1016/j.antiviral.2018.04.004[Crossref], [PubMed], [CAS], Google Scholar.198bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXnslOntrc%253D&md5=ccd9ad86ef8a1baf078e21747edef73dThe evolution of nucleoside analogue antivirals: A review for chemists and non-chemists. Part 1: Early structural modifications to the nucleoside scaffoldSeley-Radtke, Katherine L.; Yates, Mary K.Antiviral Research (2018), 154 (), 66-86CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)A review. This is the first of two invited articles reviewing the development of nucleoside-analog antiviral drugs, written for a target audience of virologists and other non-chemists, as well as chemists who may not be familiar with the field. Rather than providing a simple chronol. account, we have examd. and attempted to explain the thought processes, advances in synthetic chem. and lessons learned from antiviral testing that led to a few mols. being moved forward to eventual approval for human therapies, while others were discarded. The present paper focuses on early, relatively simplistic changes made to the nucleoside scaffold, beginning with modifications of the nucleoside sugars of Ara-C and other arabinose-derived nucleoside analogs in the 1960's. A future paper will review more recent developments, focusing esp. on more complex modifications, particularly those involving multiple changes to the nucleoside scaffold. We hope that these articles will help virologists and others outside the field of medicinal chem. to understand why certain drugs were successfully developed, while the majority of candidate compds. encountered barriers due to low-yielding synthetic routes, toxicity or other problems that led to their abandonment.(c) Seley-Radtke, K.; Yates, M. K. The evolution of nucleoside analogue antivirals: a review for chemists and non-chemists. Part II: Complex modifications to the nucleoside scaffold. Antiviral Res. 2019, 162, 5– 21, DOI: 10.1016/j.antiviral.2018.11.016[Crossref], [PubMed], [CAS], Google Scholar.198chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisFSntrzL&md5=26d398d67fa3ae4c54318057eb18b35fThe evolution of antiviral nucleoside analogues: A review for chemists and non-chemists. Part II: Complex modifications to the nucleoside scaffoldYates, Mary K.; Seley-Radtke, Katherine L.Antiviral Research (2019), 162 (), 5-21CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)This is the second of two invited articles reviewing the development of nucleoside analog antiviral drugs, written for a target audience of virologists and other non-chemists, as well as chemists who may not be familiar with the field. As with the first paper, rather than providing a chronol. account, we have chosen to examine particular examples of structural modifications made to nucleoside analogs that have proven fruitful as various antiviral, anticancer, and other therapeutics. The first review covered the more common, and in most cases, single modifications to the sugar and base moieties of the nucleoside scaffold. This paper focuses on more recent developments, esp. nucleoside analogs that contain more than one modification to the nucleoside scaffold. We hope that these two articles will provide an informative historical perspective of some of the successfully designed analogs, as well as many candidate compds. that encountered obstacles.(d) Li, G.; Yue, T.; Zhang, P.; Gu, W.; Gao, L.-J.; Tan, L. Drug discovery of nucleos(t)ide antiviral agents: dedicated to Prof. Dr. Erik De Clercq on occasion of his 80th birthday. Molecules 2021, 26, 923, DOI: 10.3390/molecules26040923[Crossref], [PubMed], [CAS], Google Scholar.198dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXltFWktr4%253D&md5=c3fca1064f90ee94443ebd7b1e93f25eDrug discovery of nucleos(t)ide antiviral agents: dedicated to Prof. Dr. Erik De Clercq on occasion of his 80th birthdayLi, Guangdi; Yue, Tingting; Zhang, Pan; Gu, Weijie; Gao, Ling-Jie; Tan, LiMolecules (2021), 26 (4), 923CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)A review. Nucleoside and nucleotide analogs are essential antivirals in the treatment of infectious diseases such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), herpes simplex virus (HSV), varicella-zoster virus (VZV), and human cytomegalovirus (HCMV). To celebrate the 80th birthday of Prof. Dr. Erik De Clercq on 28 March 2021, this review provides an overview of his contributions to eight approved nucleos(t)ide drugs: (i) three adenosine nucleotide analogs, namely tenofovir disoproxil fumarate (Viread) and tenofovir alafenamide (Vemlidy) against HIV and HBV infections and adefovir dipivoxil (Hepsera) against HBV infections; (ii) two thymidine nucleoside analogs, namely brivudine (Zostex) against HSV-1 and VZV infections and stavudine (Zerit) against HIV infections; (iii) two guanosine analogs, namely valacyclovir (Valtrex, Zelitrex) against HSV and VZV and rabacfosadine (Tanovea-CA1) for the treatment of lymphoma in dogs; and (iv) one cytidine nucleotide analog, namely cidofovir (Vistide) for the treatment of HCMV retinitis in AIDS patients. Although adefovir dipivoxil, stavudine, and cidofovir are virtually discontinued for clin. use, tenofovir disoproxil fumarate and tenofovir alafenamide remain the most important antivirals against HIV and HBV infections worldwide. Overall, the broad-spectrum antiviral potential of nucleos(t)ide analogs supports their development to treat or prevent current and emerging infectious diseases worldwide.(e) Guinan, M.; Benckendorff, C.; Smith, M.; Miller, G. J. Recent advances in the chemical synthesis and evaluation of anticancer nucleoside analogues. Molecules 2020, 25, 2050, DOI: 10.3390/molecules25092050[Crossref], [CAS], Google Scholar198ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtFWgurvK&md5=5173b380500853de9410bc6beaf6d9b3Recent advances in the chemical synthesis and evaluation of anticancer nucleoside analoguesGuinan, Mieke; Benckendorff, Caecilie; Smith, Mark; Miller, Gavin J.Molecules (2020), 25 (9), 2050CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)A review. Nucleoside analogs have proven to be highly successful chemotherapeutic agents in the treatment of a wide variety of cancers. Several such compds., including gemcitabine and cytarabine, are the go-to option in first-line treatments. However, these materials do have limitations and the development of next generation compds. remains a topic of significant interest and necessity. Herein, we discuss recent advances in the chem. synthesis and biol. evaluation of nucleoside analogs as potential anticancer agents. Focus is paid to 4'-heteroatom substitution of the furanose oxygen, 2'-, 3'-, 4'- and 5'-position ring modifications and the development of new prodrug strategies for these materials.
- 199(a) Garrett, E. R.; Seydel, J. K.; Sharpen, A. J. The acid-catalyzed solvolysis of pyrimidine nucleosides. J. Org. Chem. 1966, 31, 2219– 2227, DOI: 10.1021/jo01345a033[ACS Full Text.], [CAS], Google Scholar199ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF28XksVOqurk%253D&md5=dc0e63159bfb8a7b925ba3a994504ea7The acid-catalyzed solvolysis of pyrimidine nucleosidesGarrett, Edward R.; Seydel, Joachim K.; Sharpen, Alan J.Journal of Organic Chemistry (1966), 31 (7), 2219-27CODEN: JOCEAH; ISSN:0022-3263.The kinetics of acid-catalyzed solvolysis of various pyrimidine nucleosides were studied at various temps. and specific acid catalysis was established for all compds. except 5-hydroxyuridine which exhibited pH-independent solvolysis. Acid stability is markedly affected by the no. of OH groups in the sugar ring with complete hydroxylation of the sugar preventing degradation under the conditions used. The stereochemistry of the 3'-OH exerted a significant effect on the rate of solvolysis of 2'-deoxy-D-erythro-pentosides. Both electroneg. and electropos. substituents in the 5 position of the pyrimidine ring increased the rate of acid-catalyzed solvolysis relative to the unsubstituted 2'-deoxyuridine. The nucleosides solvolyzed at the glycoside link yielding the corresponding uracil and degraded sugar as products. An exception was 5-iodouridine which was transformed to uridine. The mechanism of glycosylamine hydrolysis in acid media is not clear; however, the substituent effects observed can be explained in terms of reactivity of various proposed intermediates in the degradation sequence.(b) Zoltewicz, J. A.; Clark, D. F.; Sharpless, T. W.; Grahe, G. Kinetics and mechanism of the acid-catalyzed hydrolysis of some purine nucleosides. J. Am. Chem. Soc. 1970, 92, 1741– 1750, DOI: 10.1021/ja00709a055[ACS Full Text.], [CAS], Google Scholar199bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE3cXhtlejtbY%253D&md5=c0b19917b35108cfb6cc95d2951d90bbKinetics and mechanism of the acid-catalyzed hydrolysis of some purine nucleosidesZoltewicz, John A.; Clark, D. Fred; Sharpless, Thomas W.; Grahe, GerwaltJournal of the American Chemical Society (1970), 92 (6), 1741-50CODEN: JACSAT; ISSN:0002-7863.Rates of acid-catalyzed hydrolysis were obtained by spectrophotometric methods for the natural nucleosides guanosine (Guo), 2'-deoxyguanosine (dGuo), and 2'-deoxyadenosine (dAdo) and for betaines, 7-methylguanosine (7MeGuo) (I) and 7-methyl-2'-deoxyguanosine (7MedGuo) (II), as well as 1,7-dimethylguanosinium iodide (1,7diMeGuoI). In solvolyzing to a purine and ribose or deoxyribose, all show specific hydronium ion catalysis over acidity regions where mono-and dicationic for ms of substrate are present. Rate profiles for Guo, dGuo, and dAdo are linear even when pH ≃ pKa. 7MeGuo and 1,7diMeGuoI undergo pH-independent hydrolysis in weakly acidic soln. 7MedGuo shows two regions linearly dependent on acidity and a pH-independent region. Kinetic and equil. pKa values for 7MedGuo are identical. Guo, 7MeGuo, and 1,7diMeGuoI hydrolyze at essentially identical rates at low pH. While dGuo is 520 times more reactive than Guo, dAdo and dGuo have similar reactivity. These nucleosides hydrolyze by a mechanism involving preequil. protonation of the purine followed by rate-limiting purine-glycosyl bond cleavage.(c) Garrett, E. R.; Mehta, P. Solvolysis of adenine nucleosides. I. Effects of sugars and adenine substituents on acid solvolyses. J. Am. Chem. Soc. 1972, 94, 8532– 8541, DOI: 10.1021/ja00779a040[ACS Full Text.], [CAS], Google Scholar199chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE3sXjtVWhtg%253D%253D&md5=43b80f53b4755f74b1b3cdb982e90c14Solvolysis of adenine nucleosides. I. Effects of sugars and adenine substituents on acid solvolysesGarrett, Edward R.; Mehta, P. J.Journal of the American Chemical Society (1972), 94 (24), 8532-41CODEN: JACSAT; ISSN:0002-7863.The acidic solvolyses of 2',3'-dideoxyadenosine > 2'-deoxyadenosine > 9-β-D-psicofuranosyladenine » 3'-deoxyadenosine > 8-bromoadenosine > 9-β-D-arabinofuranosyladenine ∼ 2-chloroadenosine ∼ N6-methyladenosine ⪆ adenosine ∼ 2-methyladenosine > 1-methyladenosine ∼ N6,N6-dimethyladenosine ⪆ 9-β-D-xylofuranosyladenine > 8-methoxyadenosine ∼ 2'-C-methyladenosine gave the resp. sugar and stable adenine moiety except in the case of where the resultant 1-methyladenine was more slowly transformed into 5-aminoimidazole-4-N'-methylcarboxamidine. The ranking of relative activities are given above for 80° in 0.10M HCl. Only specific acid catalyzed solvolyses of the protonated and non-protonated species were obsd. and there was no max. in solvolysis rate in the low pH region, supporting the argument against a Schiff base intermediate subsequent to ethereal oxygen attack. The probability of an A-1 mechanism for solvolyses of diprotonated adenine nucleosides with protons on the nitrogens in the 1 and 7 positions was favored by the fact that the entropies of activation, ΔS⧺, were close to zero. Although the inductive effect of the 2'-OH inhibited acid solvolysis, a less significant increase in reactivity was introduced by the substitution of a hydrogen for the 3'-OH. The effects of substituents on the pyrimidine ring lead to only minor effects in reactivity whereas substitution of Br or MeO on C-8 of the imidazole portion has a more pronounced effect. The 1-methyladenosine cation solvolyzes in acid at about the same rate as the adenosine cation strongly suggesting that it is the 1-protonated form of the latter that reacts with a second proton to result in a solvolyzing dication.(d) York, J. L. Effect of the structure of the glycon on the acid-catalyzed hydrolysis of adenine nucleosides. J. Org. Chem. 1981, 46, 2171– 2173, DOI: 10.1021/jo00323a040[ACS Full Text.], [CAS], Google Scholar199dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL3MXhvFalsLc%253D&md5=891eee07185cd588fe3aac2849f1a0d0Effect of the structure of the glycon on the acid-catalyzed hydrolysis of adenine nucleosidesYork, J. LyndalJournal of Organic Chemistry (1981), 46 (10), 2171-3CODEN: JOCEAH; ISSN:0022-3263.The second order rate consts. were detd. for the acid-catalyzed hydrolysis at 40° of 10 adenine furanosides and 1 pyranoside. Lability of the glycosyl-adenine bond was correlated with the configuration of the adenine with respect to the 2' and/or 3' hydroxyls, the sterically unfavorable all cis arrangement being most labile. Removal of the 2', 3', or 5' hydroxyls increases the rate of hydrolysis. A reverse D solvent isotope effect was obsd. for the anomeric 2'-deoxyribonucleosides. The entropy of activation was + 1.16 eu and + 4.39 eu for the furanoside and pyranoside of β and α-2'-deoxyribosyladenine, resp. The data are consistent with the A-1 mechanism of hydrolysis.(e) Gates, K. S. An overview of chemical processes that damage cellular DNA: spontaneous hydrolysis, alkylation, and reactions with radicals. Chem. Res. Toxicol. 2009, 22, 1747– 1760, DOI: 10.1021/tx900242k[ACS Full Text], [CAS], Google Scholar199ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtFemu7bI&md5=0fb1b99341b7f09b6b5f70e5f9d0ffcbAn overview of chemical processes that damage cellular DNA: Spontaneous hydrolysis, alkylation, and reactions with radicalsGates, Kent S.Chemical Research in Toxicology (2009), 22 (11), 1747-1760CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)A review. The sequence of heterocyclic bases on the interior of the DNA double helix constitutes the genetic code that drives the operation of all living organisms. With this said, it is not surprising that chem. modification of cellular DNA can have profound biol. consequences. Therefore, the org. chem. of DNA damage is fundamentally important to diverse fields including medicinal chem., toxicol., and biotechnol. This review is designed to provide a brief overview of the common types of chem. reactions that lead to DNA damage under physiol. conditions.
- 200Pogocki, D.; Schöneich, C. Chemical stability of nucleic acid-derived drugs. J. Pharm. Sci. 2000, 89, 443– 456, DOI: 10.1002/(SICI)1520-6017(200004)89:4<443::AID-JPS2>3.3.CO;2-N[Crossref], [PubMed], [CAS], Google Scholar200https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXis12ktb0%253D&md5=de5ac9d7a5951d7111e2e3b30307efb0Chemical stability of nucleic acid-derived drugsPogocki, Dariusz; Schoneich, ChristianJournal of Pharmaceutical Sciences (2000), 89 (4), 443-456CODEN: JPMSAE; ISSN:0022-3549. (Wiley-Liss, Inc.)A review with 124 refs. Nucleic acid-derived drugs exhibit both chem. and phys. instability. This mini-review focuses on the prevalent hydrolytic and oxidative pathways of chem. degrdn. as they are affected by various endogenous (primary structure, chem. modifications in bases, sugars and phosphate residues) and exogenous (pH, buffer concn., metal cation presence, oxygen presence) factors.
- 201(a) Minami, T.; Nakagawa, H.; Nabeshima, M.; Kadota, E.; Namikawa, K.; Kawaki, H.; Okazaki, Y. Nephrotoxicity induced by adenine and its analogues: relationship between structure and renal injury. Biol. Pharm. Bull. 1994, 17, 1032– 1037, DOI: 10.1248/bpb.17.1032[Crossref], [PubMed], [CAS], Google Scholar.201ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXivFymurs%253D&md5=5d1a870355e81816ed27b5ef36926756Nephrotoxicity induced by adenine and its analogs: relationship between structure and renal injuryMinami, Takeshi; Nakagawa, Hirofumi; Nabeshima, Masayoshi; Kadota, Eizi; Namikawa, Kiyohiro; Kawaki, Hideko; Okazaki, YukoBiological & Pharmaceutical Bulletin (1994), 17 (8), 1032-7CODEN: BPBLEO; ISSN:0918-6158. (Pharmaceutical Society of Japan)Twenty-four adenine analogs were administered to mice and the relation between the structure of the analogs and the occurrence of renal injury was examd. Plasma urea nitrogen (UN) and creatinine levels were measured 24 h after oral administration of the analogs. Both levels increased in the adenine-, 8-azaadenine-, isoguanine-, or 6-dimethylaminopurine (6-DMAP)-administered group, but did not increase in the other analog groups. From light microscopy, the damages of tubuli, mainly of proximal tubuli, were obsd. in the kidneys of these 4 groups. The common property of these compds. is the strong basicity of nitrogen which binds the 6-position of the purine ring. Furthermore, UN and creatinine increased time-dependently with i.v. administration of isoguanine. When adenine was i.v. administered, UN slightly increased at 1 h, but creatinine was unchanged. No changes were obsd. in the 6-DMAP- or 8-azaadenine-administered group. The basicity of nitrogen which binds to the 6-position of the purine ring is thus considered to be related to the occurrence of renal injury with oral administration, and isoguanine has high affinity with the kidney.(b) Philips, F. S.; Thiersch, J. B.; Bendich, A.; Borgatta, M. Adenine intoxication in relation to in vivo formation and deposition of 2,8-dioxyadenine in renal tubules. J. Pharmacol. Exp. Ther. 1952, 104, 20– 30[PubMed], [CAS], Google Scholar201bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaG38XisVWktQ%253D%253D&md5=08892515005158b29a9cc750dfd20d2eAdenine intoxication in relation to in vivo formation and deposition of 2,8-dioxyadenine in renal tubulesPhilips, Frederick S.; Thiersch, John B.; Bendich, Aaron; Borgatta, MarieJournal of Pharmacology and Experimental Therapeutics (1952), 104 (), 20-30CODEN: JPETAB; ISSN:0022-3565.In mice and rats, adenine except in quite small doses is nephrotoxic as the result of its in vivo oxidation to 2,8-dioxyadenine and deposition of the latter as cryst. occlusions in the renal tubules. The manifold effects previously ascribed to adenine intoxication are probably secondary complications of uremia.
- 202(a) Frank, K. B.; Connell, E. V.; Holman, M. J.; Huryn, D. M.; Sluboski, B. C.; Tam, S. Y.; Todaro, L. J.; Weigele, M.; Richman, D. D.; Mitsuya, H.; Broder, S.; Sim, I. S. Anabolism and mechanism of action of Ro24–5098, an isomer of 2′,3′-dideoxyadenosine (ddA) with anti-HIV activity. Ann. N. Y. Acad. Sci. 1990, 616, 408– 414, DOI: 10.1111/j.1749-6632.1990.tb17860.x[Crossref], [PubMed], [CAS], Google Scholar.202ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXlt1Kjur0%253D&md5=f9cbe05f5870d422ce8b29a45091e5c1Anabolism and mechanism of action of Ro 24-5098, an isomer of 2',3'-dideoxyadenosine (ddA) with anti-HIV activityFrank, Karl B.; Connell, Edward V.; Holman, Michael J.; Huryn, Donna M.; Sluboski, Barbara C.; Tam, Steve Y.; Todaro, Louis J.; Weigele, Manfred; Richman, Douglas D.; et al.Annals of the New York Academy of Sciences (1990), 616 (AIDS: Anti-HIV Agents, Ther., Vaccines), 408-14CODEN: ANYAA9; ISSN:0077-8923.A review with 15 refs. discussing, Ro 24-5098 (IsoddA) (I) which exhibits stability at low pH that is superior to ddA. Furthermore, IsoddA is highly resistant to enzymic degrdn. and possesses moderate anti-HIV activity in vitro. In CEM cells, phosphorylation of IsoddA to the expected antiviral metabolite, the triphosphate, occurs approx. one-third to one-fourth as readily as phosphorylation of ddA. Greater chem. and biochem. stability of the isonucleoside, however, may provide greater antiviral potency in vivo. The triphosphate of IsoddA inhibits HIV reverse transcriptase selectively with respect to DNA polymerase α. Future development of this compd. will depend upon the interaction of IsoddATP with mammalian DNA polymerases β and γ as well as toxicol. studies in animals.(b) Andrade, C. H.; de Freitas, L. M.; de Oliveira, V. Twenty-six years of HIV science: an overview of anti-HIV drugs metabolism. Braz. J. Pharm. Sci. 2011, 47, 209– 230, DOI: 10.1590/S1984-82502011000200003[Crossref], [CAS], Google Scholar.202bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXht1GktbjL&md5=4b86aa5d5680318af455f3b8b3450a9cTwenty-six years of HIV science: an overview of anti-HIV drugs metabolismAndrade, Carolina Horta; Medeiros de Freitas, Lenis; de Oliveira, ValeriaBrazilian Journal of Pharmaceutical Sciences (2011), 47 (2), 209-230CODEN: BJPSC3; ISSN:1984-8250. (Universidade de Sao Paulo, Faculdade de Ciencias Farmaceuticas)A review. From the identification of HIV as the agent causing AIDS, to the development of effective antiretroviral drugs, the scientific achievements in HIV research over the past twenty-six years have been formidable. Currently, there are twenty-five anti-HIV compds. which have been formally approved for clin. use in the treatment of AIDS. These compds. fall into six categories: nucleoside reverse transcriptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), cell entry inhibitors or fusion inhibitors (FIs), co-receptor inhibitors (CRIs), and integrase inhibitors (INIs). Metab. by the host organism is one of the most important determinants of the pharmacokinetic profile of a drug. Formation of active or toxic metabolites will also have an impact on the pharmacol. and toxicol. outcomes. Therefore, it is widely recognized that metab. studies of a new chem. entity need to be addressed early in the drug discovery process. This paper describes an overview of the metab. of currently available anti-HIV drugs.(c) Martin, J. C.; Hitchcock, M. J. M.; De Clercq, E.; Prusoff, W. H. Early nucleoside reverse transcriptase inhibitors for the treatment of HIV: A brief history of stavudine (D4T) and its comparison with other dideoxynucleosides. Antiviral Res. 2010, 85, 34– 38, DOI: 10.1016/j.antiviral.2009.10.006[Crossref], [PubMed], [CAS], Google Scholar202chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXnvFCmtA%253D%253D&md5=5323ff19629456a9039a3572cd63c78fEarly nucleoside reverse transcriptase inhibitors for the treatment of HIV: A brief history of stavudine (D4T) and its comparison with other dideoxynucleosidesMartin, John C.; Hitchcock, Michael J. M.; De Clercq, Erik; Prusoff, William H.Antiviral Research (2010), 85 (1), 34-38CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)A review. The occasion of this 25th anniversary issue encouraged us to reminisce about the important history of the discovery of the dideoxynucleoside analogs for the treatment of HIV/AIDS and to chronicle our thoughts about a particular exciting and rewarding period of our scientific careers. Following the identification of the anti-HIV activity of zidovudine (AZT), we participated in the urgent quest to discover optimal treatments of HIV infection and AIDS. A no. of previously synthesized nucleoside analogs were comparatively evaluated, and stavudine (D4T) emerged as a promising candidate for development. Following clin. evaluation, D4T became a mainstay of the initial antiretroviral combination therapy, prolonging and saving numerous lives. It has only recently been supplanted by better-tolerated treatments. This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, vol. 85, issue 1, 2010.
- 203Hirt, D.; Bardin, C.; Diagbouga, S.; Nacro, B.; Hien, H.; Zoure, E.; Rouet, F.; Ouiminga, A.; Urien, S.; Foulongne, V.; Van De Perre, P.; Treuyer, J.; Msellati, P. Didanosine population pharmacokinetics in west african human immunodeficiency virus-infected children administered once-daily tablets in relation to efficacy after one year of treatment. Antimicrob. Agents Chemother. 2009, 53, 4399– 4406, DOI: 10.1128/AAC.01187-08[Crossref], [PubMed], [CAS], Google Scholar203https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXht1KkurvE&md5=0a95237e7134b29277e43d32b359cd6aDidanosine population pharmacokinetics in West African human immunodeficiency virus-infected children administered once-daily tablets in relation to efficacy after one year of treatmentHirt, Deborah; Bardin, Christophe; Diagbouga, Serge; Nacro, Boubacar; Hien, Herve; Zoure, Emmanuelle; Rouet, Francois; Ouiminga, Adama; Urien, Saik; Foulongne, Vincent; Van De Perre, Philippe; Treluyer, Jean-Marc; Msellati, PhilippeAntimicrobial Agents and Chemotherapy (2009), 53 (10), 4399-4406CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)Our objective was to study didanosine pharmacokinetics in children after the administration of tablets, the only formulation available in Burkina Faso for which data are missing, and to establish relationships between doses, plasma drug concns., and treatment effects (efficacy/toxicity). Didanosine concns. were measured for 40 children after 2 wk and for 9 children after 2 to 5 mo of treatment with a didanosine-lamivudine-efavirenz combination. A population pharmacokinetic model was developed with NONMEM. The link between the maximal concn. of the drug in plasma (Cmax), the area under the concn.-time curve (AUC), and the decrease in human immunodeficiency virus (HIV) type 1 RNA levels after 12 mo of treatment was evaluated. The threshold AUC that improved efficacy was detd. by the use of a Wilcoxon test for HIV RNA, and an optimized dosing schedule was simulated. Didanosine pharmacokinetics was best described by a one-compartment model with first-order absorption and elimination. The apparent clearance and vol. of distribution were higher for tablets, probably due to a lower bioavailability with tablets than with pediatric powder. The decrease in the viral load after 12 mo of treatment was significantly correlated with the didanosine AUC and Cmax (P ≤ 0.02) during the first weeks of treatment. An AUC of > 0.60 mg/L/h was significantly linked to a greater decrease in the viral load (a decrease of 3 log10 vs. 2.4 log10 copies/mL; P = 0.03) than that with a lower AUC. A didanosine dose of 360 mg/m2 administered as tablets should be a more appropriate dose than 240 mg/m2 to improve efficacy for these children. However, data on adverse events with this dosage are missing.
- 204(a) Kelley, J. A.; Litterst, C. L.; Roth, J. S.; Vistica, D. T.; Poplack, D. G.; Cooney, D. A.; Nadkarni, M.; Balis, F. M.; Broder, S.; Johns, D. G. The disposition and metabolism of 2′,3′-dideoxycytidine, an in vitro inhibitor of human T-lymphotrophic virus type III infectivity, in mice and monkeys. Drug Metab. Dispos. 1987, 15, 595– 601[PubMed], [CAS], Google Scholar.204ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1cXjtFaitg%253D%253D&md5=8afe4c7180c231a954dae698d99083c0The disposition and metabolism of 2',3'-dideoxycytidine, an in vitro inhibitor of human T-lymphotrophic virus type III infectivity, in mice and monkeysKelley, James A.; Litterst, Charles L.; Roth, Jeri S.; Vistica, David T.; Poplack, David G.; Cooney, David A.; Nadkarni, Mohan; Balis, Frank M.; Broder, Samuel; Johns, David G.Drug Metabolism and Disposition (1987), 15 (5), 595-601CODEN: DMDSAI; ISSN:0090-9556.The pharmacokinetics and metab. of the anti-human T-lymphotrophic virus type III/lymphadenopathy-assocd. virus agent 2',3-dideoxycytidine were examd. in BDF1 mice and rhesus monkeys, with ancillary enzyme studies carried out on tissue derived from both the latter species and also from human subjects. For the pharmacokinetic studies, 2',3'-dideoxycytidine and its catabolic product 2',3'-dideoxyuridine were sepd. and measured in plasma, urine, and cerebrospinal fluid by a reverse HPLC method. For metabolic studies, 3H-labeled drug (labeled in the 5- and 6-positions of the pyrimidine ring) was employed, utilizing an ion exchange HPLC anal. method suitable for the sepn. of the parent nucleoside from its mono-, di-, and triphosphates in cell exts. and in tissue homogenates. The drug was rapidly cleared from plasma in a biphasic manner (terminal t1/2 in BDF1 mice and rhesus monkeys of 67 min and 109 min, resp.) following an i.v. bolus dose of 325 mg/m2. This 2-compartment open model was predictive of plasma concns. during long term i.p. infusions in mice. Dideoxycytidine was predominantly excreted in the urine as unchanged parent compd., although a minor urinary metabolite (2',3'-dideoxyuridine) was detected in the monkey but not in the mouse. Oral absorption of 2',3'-dideoxycytidine was rapid, with plasma levels approaching those seen after i.v. administration within 45 min in the mouse. Entry to the central nervous system was also rapid, but the cerebrospinal fluid to plasma area under concn.-time curve ratio after i.v. administration was only 0.026-0.040 in rhesus monkeys. Relatively high tissue levels were seen in mouse kidneys, pancreas, and liver after either single bolus i.v. injection or long-term (7-day) i.p. infusion. The drug appeared in tissues mainly as the parent nucleoside, with its pharmacol. active anabolite (2',3'-dideoxycytidine 5'-triphosphate) accounting for only a small fraction (<2%) of retained drug.(b) Klecker, R. W., Jr.; Collins, J. M.; Yarchoan, R. C.; Thomas, R.; McAtee, N.; Broder, S.; Myers, C. E. Pharmacokinetics of 2′,3′-dideoxycytidine in patients with AIDS and related disorders. J. Clin. Pharmacol. 1988, 28, 837– 842, DOI: 10.1002/j.1552-4604.1988.tb03225.x[Crossref], [PubMed], [CAS], Google Scholar204bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL1M7lsF2juw%253D%253D&md5=e1c6b2b914395421cd15b9cc5ea2bc22Pharmacokinetics of 2',3'-dideoxycytidine in patients with AIDS and related disordersKlecker R W Jr; Collins J M; Yarchoan R C; Thomas R; McAtee N; Broder S; Myers C EJournal of clinical pharmacology (1988), 28 (9), 837-42 ISSN:0091-2700.The clinical pharmacokinetics of 2',3'-dideoxycytidine (DDC) were determined after oral and intravenous administration in ten patients with AIDS or AIDS-related complex. A high performance liquid chromatography (HPLC) analysis procedure using cation exchange extraction columns was used to measure DDC levels as low as 0.1 microM (21 ng/mL) in plasma and urine. The kinetics of DDC were linear over the dose range of 0.03 to 0.5 mg/kg. Total body clearance was 227 mL/min/m2 and did not change after 6 to 14 days of dosing. The volume of distribution at steady state was 0.54 L/kg. Plasma half-life was 1.2 hours, and bioavailability was 88%. Most (75%) of the parent drug was found unchanged in the urine. As a result, renal function could play a role in dose adjustment of DDC. Comparison is made between the kinetics of DDC and 3'-azido-2',3'-dideoxythymidine (AZT). Similarities are noted in half-life and bioavailability. However, differences are observed for total body clearance, cerebrospinal fluid penetration, volume of distribution, metabolism, and recovery in urine.
- 205(a) Marquez, V. E.; Tseng, C. K.; Mitsuya, H.; Aoki, C.; Kelley, J. A.; Ford, H.; Roth, J. S.; Broder, S.; Johns, D. G.; Driscoll, J. S. Acid-stable 2′-fluoro purine dideoxynucleosides as active agents against HIV. J. Med. Chem. 1990, 33, 978– 985, DOI: 10.1021/jm00165a015[ACS Full Text.], [CAS], Google Scholar205ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3cXhvFWnsbg%253D&md5=98df7896ad6c34fde7c15f8324422e19Acid-stable 2'-fluoro purine dideoxynucleosides as active agents against HIVMarquez, Victor E.; Tseng, Christopher K. H.; Mitsuya, Hiroaki; Aoki, Shizuko; Kelley, James A.; Ford, Harry, Jr.; Roth, Jeri S.; Broder, Samuel; Johns, David G.; Driscoll, John S.Journal of Medicinal Chemistry (1990), 33 (3), 978-85CODEN: JMCMAR; ISSN:0022-2623.2',3'-Dideoxypurine nucleosides have anti-HIV activity in vitro and the inosine analog is being clin. evaluated. The instability of these compds. toward acidic conditions complicates oral administration. The effect of the addn. of a F to the 2'-position was investigated by prepg. the fluorine-contg. 2'-erythro and 2'-threo isomers of 2',3'-dideoxyadenosine (ddA) and the threo isomer of 2',3'-dideoxyadenosine (ddI). All F-contg. compds. were indefinitely stable to acidic conditions which completely decompd. ddI and ddA in minutes. While the fluorine-contg. erythro isomer, (I), was inactive, the threo isomers, 2'-F-dd-ara-A (II) and 2'-F-dd-ara-I (III), were just as potent and active in protecting CD4+ ATH8 cells from the cytopathogenic effects of HIV-1 as the parent drugs. Exposure to pH 1 at 37° prior to testing destroyed the activity of ddA and ddI but left the anti-HIV properties of II and III unchanged. The fluorinated analogs also protected cells exposed to HIV-2 and inhibited gag gene product expression but not as effectively as the parent compds. The fluorine-contg. analogs appear to be somewhat more toxic in vitro to the antigen- and mitogen-driven proliferation of immunocompetent cells than their corresponding parent compds.(b) Marquez, V. E.; Tseng, C. K.-H.; Kelley, J. A.; Mitsuya, H.; Broder, S.; Roth, J. S.; Driscoll, J. S. 2′,3′-Dideoxy-2′-fluoro-ara-A. An acid-stable purine nucleoside active against human immunodeficiency virus (HIV). Biochem. Pharmacol. 1987, 36, 2719– 2722, DOI: 10.1016/0006-2952(87)90254-1[Crossref], [PubMed], [CAS], Google Scholar.205bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1cXhvF0%253D&md5=d5ecc6950761ff16fdcff2ca32c50de52',3'-Dideoxy-2'-fluoro-ara-A. An acid-stable purine nucleoside active against human immunodeficiency virus (HIV)Marquez, Victor E.; Tseng, Christopher K. H.; Kelley, James A.; Mitsuya, Hiroaki; Broder, Samuel; Roth, Jeri S.; Driscoll, John S.Biochemical Pharmacology (1987), 36 (17), 2719-22CODEN: BCPCA6; ISSN:0006-2952.Diastereoisomers of 2'-monofluorodideoxyadenosine (I) were prepd. and tested for acid stability and protective action against HIV-induced cytopathy in cell culture. Whereas the compd. with the down configuration (I, R = H; R1 = F) was less stable and less active than the parent compd. dideoxyadenosine, the compd. with the up configuration (I, R = F; R1 = H) was as active as the known drugs AZT (3'-azido-3'-deoxythymidine) in protection against HIV-induced cytopathy and also was stable to acid conditions, such as is encountered in the stomach. Thus, I (R = F; R1 = H) appears to be a promising drug in the management of HIV infections. Structure-activity relationship is discussed.(c) Russell, J. W.; Klunk, L. J. Comparative pharmacokinetics of new anti-HIV agents: 2′, 3′-dideoxyadenosine and 2′, 3′-dideoxyinosine. Biochem. Pharmacol. 1989, 38, 1385– 1388, DOI: 10.1016/0006-2952(89)90176-7[Crossref], [PubMed], [CAS], Google Scholar205chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1MXktlejtrw%253D&md5=bd48d88280bf38d1a269bca353a830c6Comparative pharmacokinetics of new anti-HIV agents: 2',3'-dideoxyadenosine and 2',3'-dideoxyinosineRussell, John W.; Klunk, Lewis J.Biochemical Pharmacology (1989), 38 (9), 1385-8CODEN: BCPCA6; ISSN:0006-2952.The conversion of 2',3'-dideoxyadenosine (ddA) to 2',3'-dideoxyinosine (ddI) was studied in mice to det. suitability of measuring plasma levels of ddI and to assess the bioavailability and pharmacokinetics of dDA. The conversion of ddA to ddI in collected blood plasma had a half-life of 45 min to 6 h depending on the extent of hemolysis because adenosine deaminase involved in the conversion is located mainly in erythrocytes. In vivo conversion was very fast; within 5 min after i.v. administration of 25 mg ddA/kg no ddA was detectable in blood. Thus, the pharmacokinetics of ddA can be evaluated by ddI levels in blood. Both agents administered orally were partially degraded in the stomach and showed an incomplete bioavailability.
- 206(a) Liu, P.; Sharon, A.; Chu, C. K. Fluorinated nucleosides: synthesis and biological implication. J. Fluorine Chem. 2008, 129, 743– 766, DOI: 10.1016/j.jfluchem.2008.06.007[Crossref], [PubMed], [CAS], Google Scholar.206ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtVyitrnL&md5=01c8d8c393e35144095e4c31e505dd89Fluorinated nucleosides: Synthesis and biological implicationLiu, Peng; Sharon, Ashoke; Chu, Chung K.Journal of Fluorine Chemistry (2008), 129 (9), 743-766CODEN: JFLCAR; ISSN:0022-1139. (Elsevier B.V.)The present review deals with the synthetic methodol., structural and biol. implication of carbohydrate-modified fluoronucleosides. A no. of important pharmaceuticals have been discovered and developed based on fluorinated analogs of biol. active nucleosides. The introduction of fluorine into a nucleoside structure at an appropriate position has modulated and/or improved the pharmacol. properties of a mol.(b) Wójtowicz-Rajchel, H. Synthesis and applications of fluorinated nucleoside analogues. J. Fluorine Chem. 2012, 143, 11– 48, DOI: 10.1016/j.jfluchem.2012.06.026[Crossref], [CAS], Google Scholar206bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsVyktrjE&md5=df4a032247b009439fcc6b2cab92116bSynthesis and applications of fluorinated nucleoside analoguesWojtowicz-Rajchel, HannaJournal of Fluorine Chemistry (2012), 143 (), 11-48CODEN: JFLCAR; ISSN:0022-1139. (Elsevier B.V.)The review presents the synthesis of fluorinated highly modified nucleoside analogs-carbanucleosides, arom. nucleosides, acyclic nucleosides and related derivs.
- 207Rozen, S.; Vints, I.; Lerner, A.; Hod, O.; Brothers, E. N.; Moncho, S. The chemistry of short-lived α-fluorocarbocations. J. Org. Chem. 2021, 86, 3882– 3889, DOI: 10.1021/acs.joc.0c02731[ACS Full Text], [CAS], Google Scholar207https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXksFWktbk%253D&md5=ebe1f9e22f2214d83014155f2c6da09aThe Chemistry of Short-Lived α-FluorocarbocationsRozen, Shlomo; Vints, Inna; Lerner, Ana; Hod, Oded; Brothers, Edward N.; Moncho, SalvadorJournal of Organic Chemistry (2021), 86 (5), 3882-3889CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)The present study of the chem. of short-lived α-fluorocarbocations reveals that even inactive Me carbons can serve as nucleophiles, attacking a cationic center. This, in turn, facilitates the synthesis of a cyclopropane ring in certain triterpene backbones. We report the synthesis of compds. similar to 2, contg. a bridgehead cyclopropane, and compds. of type 3 with an 11 membered bicyclic ring consisting of two bridgehead double bonds (anti-Bredt) within a triterpene skeleton. The synthesis involves three unconventional chem. processes: (a) a Me group serving as a nucleophile; (b) the unexpected and unprecedented synthesis of a strained system in the absence of an external neighboring trigger; and (c) the formation of an 11-membered bicyclic diene ring within a triterpenoid skeleton. An α-fluorocarbocation mechanism is proposed and supported by d. functional theory calcns.
- 208Johnson, S. A. Nucleoside analogues in the treatment of haematological malignancies. Expert Opin. Pharmacother. 2001, 2, 929– 943, DOI: 10.1517/14656566.2.6.929[Crossref], [PubMed], [CAS], Google Scholar208https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXkvVKmtbc%253D&md5=97874da0b9574126f88a62bc4edf32e9Nucleoside analogues in the treatment of haematological malignanciesJohnson, Stephen A.Expert Opinion on Pharmacotherapy (2001), 2 (6), 929-943CODEN: EOPHF7; ISSN:1465-6566. (Ashley Publications Ltd.)A review with refs. The nucleoside analogs are a group of antimetabolite cytotoxics which generally have to be metabolized to the equiv. nucleotide before incorporation into DNA. Cytarabine is a well established component of the treatment of acute leukemias and has its principal action on dividing cells. New formulations include a liposome encapsulated product for intrathecal use and oral cytarabine ocfosfate which may be suitable for long-term outpatient use. Pentostatin acts by causing accumulation of deoxynucleotides and, although active against hairy cell leukemia, is assocd. with a poor tolerance profile. Cladribine and fludarabine have substantial activity in the treatment of chronic lymphocytic leukemia (CLL) and low-grade non-Hodgkin's lymphoma (NHL). Fludarabine is the more thoroughly investigated of the two and is currently being developed in combination therapies for CLL and NHL and also in a combination with cytarabine for acute myeloid leukemia. Fludarabine's immunosuppressive activity is being exploited in the conditioning of patients for non-myeloablative stem cell transplantation. Gemcitabine is an established agent in the treatment of a no. of solid tumors but also has activity in haematol. malignancies which might be exploited by the use of extended infusion schedules. Newer agents including nelarabine, clofarabine and troxacitabine are undergoing clin. evaluation and show promising activity.
- 209Avramis, V. I.; Plunkett, W. 2-Fluoro-ATP: a toxic metabolite of 9-β-d-arabinoxyl-2-fluroadenine. Biochem. Biophys. Res. Commun. 1983, 113, 35– 43, DOI: 10.1016/0006-291X(83)90428-X[Crossref], [PubMed], [CAS], Google Scholar209https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL3sXks1ektbY%253D&md5=6c839f5fc3692e6e9fa68d246b6f723d2-Fluoro-ATP: a toxic metabolite of 9-β-D-arabinosyl-2-fluoroadenineAvramis, Vassilios I.; Plunkett, WilliamBiochemical and Biophysical Research Communications (1983), 113 (1), 35-43CODEN: BBRCA9; ISSN:0006-291X.Murine P388 cells incubated in vitro with the anticancer drug 9-β-D-arabinosyl-2-fluoroadenine (I) [21679-14-1] accumulated its 5'-triphosphate, F-araATP [74832-57-8], as the major phosphorylated metabolite. A new chromatog. distinct metabolite that accumulated to 10% of F-araATP levels was identified as 2-fluoro-ATP (II) [1492-62-2], by the following criteria: (1) the metabolite coeluted with the authentic compd. on anion-exchange high-performance liq. chromatog.; (2) dephosphorylation of the metabolite yielded a compd. that was chromatog. identical to 2-fluoroadenosine; (3) the compd. was sensitive to NaIO4 oxidn. Cellular incubation expts. indicated that 2-fluoroadenine [700-49-2], but not arabinosyl-2-fluorohypoxanthine [83480-48-2], was the likely intermediate in the formation of 2-fluoro-ATP.
- 210(a) Carson, D. A.; Wasson, D. B.; Esparza, L. M.; Carrera, C. J.; Kipps, T. J.; Cottam, H. B. Oral antilymphocyte activity and induction of apoptosis by 2-chloro-2′-arabino-fluoro-2′-deoxyadenosine. Proc. Natl. Acad. Sci. U. S. A. 1992, 89, 2970– 2974, DOI: 10.1073/pnas.89.7.2970[Crossref], [PubMed], [CAS], Google Scholar.210ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK38Xit1OrsL0%253D&md5=ba2408150a5c7b3e001d65cdb64607afOral antilymphocyte activity and induction of apoptosis by 2-chloro-2'-arabino-fluoro-2'-deoxyadenosineCarson, Dennis A.; Wasson, D. Bruce; Esparza, Lucia M.; Carrera, Carlos J.; Kipps, Thomas J.; Cottam, Howard B.Proceedings of the National Academy of Sciences of the United States of America (1992), 89 (7), 2970-4CODEN: PNASA6; ISSN:0027-8424.2-Chlorodeoxyadenosine (CdA) is active in chronic lymphocytic leukemia, hairy-cell leukemia, and low-grade lymphomas. In part, this spectrum of activity may be attributable to the selective toxicity of CdA to nondividing lymphoctytes and monocytes. However, CdA is unstable at acidic pH and is degraded by bacterial nucleoside phosphorylases. The present expts. demonstrate that the 2'-arabino-fluoro deriv. of CdA, designated CAFdA, is also directly toxic to quiescent lymphocytes and macrophages. Unlike CdA, CAFdA was stable at pH 2 and resisted degrdn. by Escherichia coli nucleoside phosphorylase. Cell killing was preceded by the formation of DNA strand breaks and could be prevented by supplementation of the medium with deoxycytidine. The initial DNA damage initiated the pattern of oligonucleosomal DNA fragmentation characteristic of apoptosis. Mutant lymphoblasts, deficient in deoxycytidine kinase, with elevated cytoplasmic 5'-nucleotidase, or with expanded deoxynucleotide pools secondary to increased ribonucleotidase, or with expanded deoxynucleotide pools secondary to increased ribonucleotide reductase activity, were cross-resistant to both CAFdA and CdA toxicity. One-week oral treatment with CAFdA (1 mg/mL in drinking water) achieved an av. plasma concn. of 0.56 μM and eliminated 90% of chronic lymphocytic leukemia cells transplanted into severe combined immunodeficiency (scid) mice. Under the same conditions, CdA was much less active. Collectively, these results suggest that CAFdA could be effective as and oral agent in indolent lymphoproliferative diseases and in autoimmune diseases where lymphocyte and monocyte depletion is desirable.(b) Lindemalm, S.; Liliemark, J.; Juliusson, J.; Larsson, R.; Albertioni, F. Cytotoxicity and pharmacokinetics of cladribine metabolite, 2-chloroadenine, in patients with leukemia. Cancer Lett. 2004, 210, 171– 177, DOI: 10.1016/j.canlet.2004.03.007[Crossref], [PubMed], [CAS], Google Scholar210bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXks1WrsLk%253D&md5=33704489f7136957ac850290648c817aCytotoxicity and pharmacokinetics of cladribine metabolite, 2-chloroadenine in patients with leukemiaLindemalm, Synnove; Liliemark, Jan; Juliusson, Gunnar; Larsson, Rolf; Albertioni, FreidounCancer Letters (Amsterdam, Netherlands) (2004), 210 (2), 171-177CODEN: CALEDQ; ISSN:0304-3835. (Elsevier)The nucleoside analog 2-chlorodeoxyadenosine (Cladribine, CdA) is used in the treatment of patients with several hematol. malignancies. After administration of CdA, the major catabolite measured in plasma and urine is 2-chloroadenine (CAde). This study was performed to det. the pharmacokinetics after oral and i.v. (iv) infusion of CdA in patients treated for chronic lymphocytic leukemia and to evaluate the toxicity of CAde to leukemia cells in vitro. CdA and CAde were also detd. in plasma from 31 patients and in urine from 16 patients with reversed-phase high-performance liq. chromatog. The toxicity of CdA and CAde was also detd. in leukemic cells from 7 patients by fluorometric microculture cytotoxicity assay. Five times more CAde was quantified after oral treatment compared with an iv infusion of CdA. After iv infusion, the half-life was the same for CdA and CAde, but after oral administration the half-life was doubled for CAde. Excreted amt. of CAde in urine constituted about 1.1% after iv infusion and 4.7% after oral CdA treatment. In vitro exposure of leukemia cells to CAde showed that it was eight times less toxic as compared to CdA. We conclude that CAde has a lower cytotoxic effect than CdA but may contribute significantly to the cytotoxicity after oral administration.
- 211(a) Chilman-Blair, K.; Mealy, N. E.; Castaner, J. Clofarabine: treatment of acute leukemia. Drugs Future 2004, 29, 112– 120, DOI: 10.1358/dof.2004.029.02.776206[Crossref], [CAS], Google Scholar.211ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXivF2kur4%253D&md5=c9e78e3324853ff8ffb3b0da3a63e075Clofarabine: treatment of acute leukemiaChilman-Blair, K.; Mealy, N. E.; Castaner, J.Drugs of the Future (2004), 29 (2), 112-120CODEN: DRFUD4; ISSN:0377-8282. (Prous Science)A review. Clofarabine (Clofarex, 2-Cl-2'-F-araA, CAFdA) is a novel anticancer agent shown to be particularly effective in acute leukemia therapy. It is a second-generation purine nucleoside analog that works through incorporation into the DNA mol. and inhibition of further DNA synthesis via a no. of different mechanisms. Clofarabine is effective in many different cancers, and has proven efficacy in phase I studies in patients with solid tumors. However, clofarabine has demonstrated the most promise within the hematol. setting. Results from a no. of phase I/II studies indicated potent anticancer activity, particularly in the treatment of acute leukemias. Clofarabine is most often administered as a short 30-min i.v. infusion over 5 days per cycle, meaning that it can be delivered in an outpatient setting rather than requiring hospitalization (as opposed to first-generation analogs). Furthermore, children with resistant or refractory leukemia have exhibited total response rates of 28-44%. Clofarabine is well tolerated in this population, the most commonly reported side effects being nausea and vomiting, reversible hepatotoxicity and myelo-suppression. Promising results from phase I and II studies have led to the initiation of phase III studies in both adults and children with acute leukemia.(b) Bonate, P.; Arthaud, L.; Cantrell, W.; Stephenson, K.; Secrist, J. A.; Weitman, S. Discovery and development of clofarabine: a nucleoside analogue for treating cancer. Nat. Rev. Drug Discovery 2006, 5, 855– 863, DOI: 10.1038/nrd2055[Crossref], [PubMed], [CAS], Google Scholar.211bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtVajsbnL&md5=6d47f6d0f97231de14b598cdd0521fd0Discovery and development of clofarabine: a nucleoside analogue for treating cancerBonate, Peter L.; Arthaud, Larry; Cantrell, William R., Jr.; Stephenson, Katherine; Secrist, John A., III; Weitman, SteveNature Reviews Drug Discovery (2006), 5 (10), 855-863CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)A review. The treatment of acute leukemias, which are the most common pediatric cancers, has improved considerably in recent decades, with complete response rates approaching ∼90% in some cases. However, there remains a major need for treatments for patients who do not achieve or maintain complete remission, for whom the prognosis is very poor. In this article, the authors describe the challenges involved in the discovery and development of clofarabine, a second-generation nucleoside analog that received accelerated approval from the US FDA at the end of 2004 for the treatment of pediatric patients 1-21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens. It is the first such drug to be approved for pediatric leukemia in more than a decade, and the first to receive approval for pediatric use before adult use.(c) Montgomery, J. A.; Shortnacy-Fowler, A. T.; Clayton, S. D.; Riordan, J. M.; Secrist, J. A. Synthesis and biologic activity of 2′-fluoro-2-halo derivatives of 9-β-d-arabinofuranosyladenine. J. Med. Chem. 1992, 35, 397– 401, DOI: 10.1021/jm00080a029[ACS Full Text.], [CAS], Google Scholar211chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK38XhsFahtL8%253D&md5=515eff4888e6751ab623da12729df34bSynthesis and biological activity of 2'-fluoro-2-halo derivatives of 9-β-D-arabinofuranosyladenineMontgomery, John A.; Shortnacy-Fowler, Anita T.; Clayton, Sarah D.; Riordan, James M.; Secrist, John A., IIIJournal of Medicinal Chemistry (1992), 35 (2), 397-401CODEN: JMCMAR; ISSN:0022-2623.The synthesis of 2-halo-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)adenines I (R = Br, Cl) by coupling the 2,6-dihalopurine with 2-deoxy-2-fluoro-D-arabinofuranosyl bromide II followed by replacement of the 6-halogen with concomitant removal of the acyl blocking groups is described. 2-Fluoroadenine deriv. I (R = F) had to be prepd. by the diazotization-fluorination of 2-aminoadenine nucleoside III (R1 = NH2, R2 = Ac). All three nucleosides provided good increases in life span of mice inoculated with P388 leukemia. The best results were obtained when the compds. were administered q3h×8 on days 1, 5, and 9 after implantation of the leukemia cells. The 2',3'-dideoxynucleoside IV (R3 = H), prepd. by deacetylation of III (R1 = F, R2 = Ac) and deoxygenation of the resultant III (R1 = F, R2 = H) followed by removal of the benzoyl group of IV (R3 = Bz), was slightly active against HIV in cell culture.(d) Xie, C.; Plunke, W. Metabolism and actions of 2-chloro-9-(2-deoxy-2-fluoro-β-d-arabinofuranosyl)adenine in human lymphoblastoid cells. Cancer Res. 1995, 55, 2847– 2852[PubMed], [CAS], Google Scholar.211dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXmsFyksL4%253D&md5=00fb1bd957c0bb69f355089dea62a081Metabolism and actions of 2-chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)adenine in human lymphoblastoid cellsXie, Chunxi; Plunkett, WilliamCancer Research (1995), 55 (13), 2847-52CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)2-Chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)adenine (Cl-F-ara-A) is a new deoxyadenosine analog that is resistant to phosphorolytic cleavage and deamination. Studies with a variety of cell lines demonstrated that Cl-F-ara-A is a potent cytotoxic agent; in cell-free systems, its triphosphate (Cl-F-ara-ATP) inhibited DNA polymerase α and ribonucleotide reductase. To further characterize its mechanism of cytotoxicity, the present study investigated the cellular metab. of Cl-F-ara-A and the actions of its nucleotide metabolites in human T-lymphoblast leukemia CCRF-CEM cells. The mono-, di-, and triphosphates of Cl-F-ara-A accumulated in cells, with the monophosphate as its major metabolite. After washing cells into drug-free medium, the elimination of each Cl-F-ara-A nucleotide was nonlinear with a prolonged terminal phase. Incubation of CCRF-CEM cells with Cl-F-ara-A resulted in a incorporation of Cl-F-ara-AMP into DNA; a much lesser amt. was assocd. with RNA, suggesting that Cl-F-ara-A is a more DNA-directed compd. The site; of tissues of the analog triphosphate and the natural substrate dATP. At low Cl-F-ara-ATP:dATP values, incorporation was mainly in phosphodiester linkages at internal sites, whereas at higher Cl-F-ara-ATP:dATP values, Cl-F-ara-AMP was principally detected at terminal sites. Clonogenicity assays showed a strong inverse correlation between cell survival and Cl-F-ara-AMP incorporation into DNA. These results suggest that the incorporation of Cl-F-ara-A monophosphate into DNA is crit. for the cytotoxicity of Cl-ara-A.(e) Faderl, S.; Garcia-Manero, G.; Estrov, Z.; Ravandi, F.; Borthakur, G.; Cortes, J. E.; O’Brien, S.; Gandhi, V.; Plunkett, W.; Byrd, A.; Kwari, M.; Kantarjian, H. M. Oral clofarabine in the treatment of patients with higher-risk myelodysplastic syndrome. J. Clin. Oncol. 2010, 28, 2755– 2760, DOI: 10.1200/JCO.2009.26.3509[Crossref], [PubMed], [CAS], Google Scholar.211ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXoslyktbg%253D&md5=eca1a4d2a7c6b86a6bd31675c68460fdOral clofarabine in the treatment of patients with higher-risk myelodysplastic syndromeFaderl, Stefan; Garcia-Manero, Guillermo; Estrov, Zeev; Ravandi, Farhad; Borthakur, Gautam; Cortes, Jorge E.; O'Brien, Susan; Gandhi, Varsha; Plunkett, William; Byrd, Anna; Kwari, Monica; Kantarjan, Hagop M.Journal of Clinical Oncology (2010), 28 (16), 2755-2760CODEN: JCONDN; ISSN:0732-183X. (American Society of Clinical Oncology)Efficacy and toxicity profile of orally administered clofarabine were evaluated in patients with higher-risk myelodysplastic syndrome (MDS). 32 Patients were treated, of whom 22 had intermediate-2 or high-risk disease (International Prognostic Scoring System). Median age was 70 years (range, 53 to 86), nine patients had secondary MDS, and 20 patients experienced prior therapy failure with hypomethylating agents. 3 Doses of clofarabine were evaluated: 40 mg/m2, 30 mg/m2, and 20 mg/m2 daily for 5 days. Courses were repeated every 4 to 8 wk. 8 Patients (25%) achieved complete remission (CR), three had (9%) hematol. improvement (HI), and three had (9%) clin. benefit (CB; overall response rate, 43%). Responses in patients who experience treatment failure with hypomethylating agents included CR in two (10%), HI in two (10%), and CB in two patients (10%). No patients died within 6 wk of induction. Renal failure occurred in four patients in the context of myelosuppresssion-assocd. infectious complications. Common adverse events were gastrointestinal and hepatic. Myelosuppression was common, but prolonged myelosuppression (> 42 days) was rare. The toxicity profile was better with lower doses of clofarabine, whereas response rates did not differ significantly. Oral clofarabine has achieved a response rate of 43% in patients with higher-risk MDS. The optimal dose and schedule and the appropriate patient population for such therapy remain to be further defined.(f) Hermann, R.; Karlsson, M. O.; Novakovic, A. M.; Terranova, N.; Fluck, M.; Munafo, A. The clinical pharmacology of cladribine tablets for the treatment of relapsing multiple sclerosis. Clin. Pharmacokinet. 2019, 58, 283– 297, DOI: 10.1007/s40262-018-0695-9[Crossref], [PubMed], [CAS], Google Scholar211fhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtlWntrjK&md5=06e46182e31de49c64ed4add6cb44c8eThe Clinical Pharmacology of Cladribine Tablets for the Treatment of Relapsing Multiple SclerosisHermann, Robert; Karlsson, Mats O.; Novakovic, Ana M.; Terranova, Nadia; Fluck, Markus; Munafo, AlainClinical Pharmacokinetics (2019), 58 (3), 283-297CODEN: CPKNDH; ISSN:0312-5963. (Springer International Publishing AG)A review. Cladribine Tablets (MAVENCLAD) are used to treat relapsing multiple sclerosis (MS). The recommended dose is 3.5 mg/kg, consisting of 2 annual courses, each comprising 2 treatment weeks 1 mo apart. We reviewed the clin. pharmacol. of Cladribine Tablets in patients with MS, including pharmacokinetic and pharmacometric data. Cladribine Tablets are rapidly absorbed, with a median time to reach max. concn. (Tmax) of 0.5 h (range 0.5-1.5 h) in fasted patients. When administered with food, absorption is delayed (median Tmax 1.5 h, range 1-3 h), and max. concn. (Cmax) is reduced by 29% (based on geometric mean). Area under the concn.-time curve (AUC) is essentially unchanged. Oral bioavailability of cladribine is approx. 40%, pharmacokinetics are linear and time-independent, and vol. of distribution is 480-490 L. Plasma protein binding is 20%, independent of cladribine plasma concn. Cladribine is rapidly distributed to lymphocytes and retained (either as parent drug or its phosphorylated metabolites), resulting in approx. 30- to 40-fold intracellular accumulation vs. extracellular concns. as early as 1 h after cladribine exposure. Cytochrome P 450-mediated biotransformation of cladribine is of minor importance. Cladribine elimination is equally dependent on renal and non-renal routes. In vitro studies indicate that cladribine efflux is minimally P-glycoprotein (P-gp)-related, and clin. relevant interactions with P-gp inhibitors are not expected. Cladribine distribution across membranes is primarily facilitated by equilibrative nucleoside transporter (ENT) 1, concentrative nucleoside transporter (CNT) 3 and breast cancer resistance protein (BCRP), and there is no evidence of any cladribine-related effect on heart rate, atrioventricular conduction or cardiac repolarisation (QTc interval prolongation). Cladribine Tablets are assocd. with targeted lymphocyte redn. and durable efficacy, with the exposure-effect relationship showing the recommended dose is appropriate in reducing relapse risk.
- 212(a) Bolwell, B. J.; Cassileth, P. A.; Gale, R. P. High dose cytarabine: a review. Leukemia 1988, 2, 253– 260[PubMed], [CAS], Google Scholar.212ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL1c3jtFOmsQ%253D%253D&md5=88ea5104cf80d212fac1032c1dc6559dHigh dose cytarabine: a reviewBolwell B J; Cassileth P A; Gale R PLeukemia (1988), 2 (5), 253-60 ISSN:0887-6924.High dose cytarabine (HDARAC) therapy is used increasingly to treat hematologic malignancies. Recent data indicate that HDARAC at doses of 2-3 g/M2 every 12 hr x 10-12 doses is of comparable or greater efficacy in remission induction as standard doses of cytarabine in acute myelogenous leukemia. HDARAC can also produce remissions in individuals resistant to conventional doses. HDARAC-containing regimens are reported to result in substantially higher long-term, disease-free survival than previous approaches to post-remission therapy, but this has not yet been confirmed in controlled trials. HDARAC is also active in acute lymphocytic leukemia. Because intravenous HDARAC achieves high levels in the spinal fluid, it is useful to treat central nervous system leukemia and may provide adequate CNS prophylaxis in acute lymphocytic leukemia. HDARAC is reported to be active in advanced non-Hodgkin lymphomas and chronic myelogenous leukemia in acute phase; optimal use in these settings is under study. HDARAC has also been combined with other drugs. Randomized trials are needed to determine whether these combinations are more effective than HDARAC alone. Apart from potent myelosuppression, the dose-limiting toxicity of HDARAC is cerebellar damage. This occurs with increased frequency in patients greater than 50 years old. HDARAC is active in hematologic malignancies and may further improve therapeutic results if combined with other drugs.(b) Capizzi, R. L.; White, J. C.; Powell, B. L.; Perrino, F. Effect of dose on the pharmacokinetic and pharmacodynamic effects of cytarabine. Semin. Hematol. 1991, 28, 54– 69[PubMed], [CAS], Google Scholar212bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXmt1amsLw%253D&md5=461fef418a4b00006d24e7aea44499dfEffect of dose on the pharmacokinetic and pharmacodynamic effects of cytarabineCapizzi, Robert L.; White, J. Courtland; Powell, Bayard L.; Perrino, FredSeminars in Hematology (1991), 28 (3, Suppl. 4), 54-69CODEN: SEHEA3; ISSN:0037-1963.A review with 100 refs. on the treatment of leukemia with cytarabine.
- 213(a) Bergmann, W.; Feeney, R. J. Contributions to the study of marine products. The nucleosides of sponges. J. Org. Chem. 1951, 16, 981– 987, DOI: 10.1021/jo01146a023[ACS Full Text.], [CAS], Google Scholar213ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaG38Xjt1OnsA%253D%253D&md5=5f079e325324ccde033e002d05d355f0Marine products. XXXII. The nucelosides of sponges. IBergmann, Werner; Feeney, Robert J.Journal of Organic Chemistry (1951), 16 (), 981-7CODEN: JOCEAH; ISSN:0022-3263.Sponges of the species Cryptotethia crypta (I) from the coast of Florida, vacuum dried at 60° (600 g.), contg. 40% ash, are ground and extd. 2 days in a Soxhlet with Me2CO, giving 9.01 g. cryst. material. It is extd. with 400 cc. boiling EtOH, leaving 1.5 g. spongothymidine (II), clusters of prisms from H2O, m. 246-7°, [α]D25 81°, 80° (17.9, 33.5 mg. in 3.09 cc. 8% NaOH), [α]D 92° (27.3 mg. in 3.09 cc. C5H5N),λmax. 269mμ. From the cooled EtOH ext. another 2.4 g. II, m. 244°, is obtained. Titrating 59.4 mg. II according to Lythgoe and Todd (C.A. 39, 912.1) results in the consumption of 49.8 mg. NaIO4 or a 1.0 molar amt. Benzoylation of 150 mg. II with BzCl and 4% NaOH gives II tribenzoate, m. 190-1°; tri-p-bromobenzoate, rod-shaped crystals, m. 251-2°. Heating 630 mg. II in 10% H2SO4 3 hrs. at 130-40° and cooling the hot filtered soln. gives thymine, m. 321° with sublimation. Concn. of the original Me3CO mother liquor gives 0.3 g. of a compd., C11H15N5O5, called spongosine (III), crystals from H2O and from EtOH, m. 192-3°, [α]D25 -42.5° (24.6 mg. in 3.09 cc. 8% NaOH), which shows 1 λmax. in 0.1 N NaOH and 2 λmax. in 0.1 N HCl. III is probably a purine analog of II. Refluxing 1 hr. 120 mg. III with 5 cc. 0.1 N H2SO4 gives what may be a methylamino.ovrddot.oxypurine, C6H7N5O (IV), m. 278°. Treating IV in H2SO4 with NaNO2 gives a deaminated compd., C6H7N4O2, needles, m. 322-5°. Extn. of 620 g. (corresponding to 280 g. organic material) air-dried I from the Bahamas with Me2CO gives 4 g. of a semi-cryst. product which is washed with C6H6 and again extd. with Me2CO, giving a product which contained little, if any, II. A sample is refluxed several hrs. with 0.1 N H2SO4, giving thymine, m. 320-1°. The final Me2CO mother liquors of the 2 I are evapd. to dryness and the residue (2-3% of I) is sapond., giving 50% unsaponifiable material contg. about 60% sterols. They are acetylated, giving acetate fractions (V) with 1.05-1.2 double bonds. V are brominated with Br in AcOH and sepd. into insol. tetrabromide (VI) and sol. dibromide (VII). From VI only a small amt. of what seems to be poriferasteryl acetate tetrabromide, m. 187°, is obtained. VII are debrominated and recrystd., giving some clionasteryl (VIII) acetate, m. 134-5°, [α]D25 -42.5° (30.8 mg. in 3.09 cc. CHCl3), which, sapond., gives the free sterol, m. 137.5-8.5°, [α]D25 -37° (33.1 mg. in 3.06 cc. CHCl3); VIII propionate m. 116-16.5°, [α]D25 -41.3° (30.7 mg., CHCl3); VIII benzoate m. 139-9.5°, [α]D25 -17° (31.4 mg., CHCl3).(b) Bergmann, W.; Burke, D. C. Contributions to the study of marine products. The nucleosides of sponges. III. Spongothymidine and spongouridine. J. Org. Chem. 1955, 20, 1501– 1507, DOI: 10.1021/jo01128a007[ACS Full Text.], [CAS], Google Scholar213bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaG28Xlt1Klug%253D%253D&md5=7fa5f57b9fd58b73b0337883e01d3600Marine products. XXXIX. The nucleosides of sponges. III. Spongothymidine and spongouridineBergmann, Werner; Burke, Derek C.Journal of Organic Chemistry (1955), 20 (), 1501-7CODEN: JOCEAH; ISSN:0022-3263.cf. C.A. 46, 5609h; 50, 7808g. Paper chromatography of certain crude fractions of the nucleosides (I) isolated from Crypotethia crypta revealed the presence of spongothymidine (II), spongosine (III), and spongouridine (IV). These I have now been sepd. I are absorbed on a Dowex-1 resin (OH- form) and eluted with a NH4OH-NH4O2CH buffer soln. (pH 9.5) which elutes III. Further elution with a buffer of pH 8.3 gives II, thymine, uracil, and IV in the order given. IV, cubic crystals, m. 226-8°, [α]D 97° (c 0.6, 8% NaOH), 126° (c 1, H2O), pK 9.3. Heating 5 mg. IV with 2 cc. 90% HCO2H 2 hrs. at 150° and paper-chromatographing the product indicate the presence of unchanged IV and some uracil. Refluxing II 3 hrs. in 5% HCl or 5 hrs. in 10% H2SO4, or heating it in a sealed tube 2 hrs. with 10% H2SO4 at 125° or with 5% HCl-MeOH 5 hrs. at 100° leaves II unchanged. Reducing 467 mg. II in 100 cc. liquid NH8 and 5 cc. EtOH with 0.4 g. Na (cf. loc. cit.) and passing the product through Dowex (H+ form) give 400 mg. of a yellow gum (V), [α]D -51°, which by paper chromatography (BuOH-EtOH-H2O and BuOH satd. with H2O) and by ionophoresis in a borate buffer is found to contain only arabinose. When treated with phenylhydrazine V gives a phenylosazone (VI), m. 154-5°, which does not depress the m.p. of the phenylosazone (VII) from ribose. The infrared absorption spectrum of VI is identical with that of VII but differs from that of xylose. Similar reduction of 5.3 mg. IV followed by paper chromatography indicates the presence of arabinose. Periodate oxidation of adenosine, guanosine, cytidine, uridine, II, and IV (20-50 mg.) in H2O with 5 cc. 0.2808N NaIO4 shows the consumption of 1 mole iodate without the formation of HCO2H. Paper ionophoresis of II gives a migration rate of 0.50 for II and 0.68 for IV. Oxidation of 23 mg. II with 1 cc. 0.26N NaIO4 after 24 hrs. gives a soln. with [α]D 16.3°; a similar oxidation of D-glucopyranosylthymine gives a soln. with [α]D 17°; oxidation of 21 mg. IV gives a soln. with [α]D 15°, and oxidation of 25 mg. uridine a soln. with [α]D 15.2°. The results indicate that II is 3-β-D-arabofuranosylthymine and IV is 3-β-D-arabofuranosyluracil.(c) Khalifa, S. A. M.; Elias, N.; Farag, M. A.; Chen, L.; Saeed, A.; Hegazy, M.-E. F.; Moustafa, M. S.; Abd El-Wahed, A.; Al-Mousawi, S. M.; Musharraf, S. G.; Chang, F.-R.; Iwasaki, A.; Suenaga, K.; Alajlani, M.; Goransson, U.; El-Seedi, H. R. Marine natural products: a source of novel anticancer drugs. Mar. Drugs 2019, 17, 491, DOI: 10.3390/md17090491[Crossref], [CAS], Google Scholar.213chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXmsVCmurs%253D&md5=d1d83b0ccc8d517511e09b38da9d42a0Marine natural products: a source of novel anticancer drugsKhalifa, Shaden A. M.; Elias, Nizar; Farag, Mohamed A.; Chen, Lei; Saeed, Aamer; Hegazy, Mohamed-Elamir F.; Moustafa, Moustafa S.; Abd El-Wahed, Aida; Al-Mousawi, Saleh M.; Musharraf, Syed G.; Chang, Fang-Rong; Iwasaki, Arihiro; Suenaga, Kiyotake; Alajlani, Muaaz; Goeransson, Ulf; El-Seedi, Hesham R.Marine Drugs (2019), 17 (9), 491CODEN: MDARE6; ISSN:1660-3397. (MDPI AG)A review. Cancer remains one of the most lethal diseases worldwide. There is an urgent need for new drugs with novel modes of action and thus considerable research has been conducted for new anticancer drugs from natural sources, esp. plants, microbes and marine organisms. Marine populations represent reservoirs of novel bioactive metabolites with diverse groups of chem. structures. This review highlights the impact of marine organisms, with particular emphasis on marine plants, algae, bacteria, actinomycetes, fungi, sponges and soft corals. Anti-cancer effects of marine natural products in in vitro and in vivo studies were first introduced; their activity in the prevention of tumor formation and the related compd.-induced apoptosis and cytotoxicities were tackled. The possible mol. mechanisms behind the biol. effects are also presented. The review highlights the diversity of marine organisms, novel chem. structures, and chem. property space. Finally, therapeutic strategies and the present use of marine-derived components, its future direction and limitations are discussed.(d) Dyshlovoy, S. A.; Honecker, F. Marine compounds and cancer: the first two decades of XXI century. Mar. Drugs 2020, 18, 20, DOI: 10.3390/md18010020
- 214(a) Sun, Y.; Sun, J.; Shi, S.; Jing, Y.; Yin, S.; Chen, Y.; Li, G.; Xu, Y.; He, Z. Synthesis, transport and pharmacokinetics of 5′-amino acid ester prodrugs of 1-β-d-arabinofuranosylcytosine. Mol. Pharmaceutics 2009, 6, 315– 325, DOI: 10.1021/mp800200a[ACS Full Text.], [CAS], Google Scholar214ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtFM%253D&md5=b0c0eb744c81107c794d9f2f7d4077afSynthesis, Transport and Pharmacokinetics of 5'-Amino Acid Ester Prodrugs of 1-β-D-ArabinofuranosylcytosineSun, Yongbing; Sun, Jin; Shi, Shiliang; Jing, Yongkui; Yin, Shiliang; Chen, Ying; Li, Gang; Xu, Youjun; He, ZhongguiMolecular Pharmaceutics (2009), 6 (1), 315-325CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)Cytarabine (1-β-D-arabinofuranosylcytosine, ara-C, 1) suffers from low oral bioavailability due to low intestinal membrane permeability and poor metabolic stability, and i.v. infusion is usually adopted as the clin. std. dosing administration. To develop an oral alternative for 1 and utilize the intestinal oligopeptide transporter 1 (PepT1), a series of 5'-amino acid ester derivs. of 1 was synthesized to clarify which modification was the most suitable to increase the oral bioavailability of 1. Their apical-to-basolateral permeability across Caco-2 cells and the antiproliferative activity with HL-60 cells were screened. 5'-Valyl prodrug 2 demonstrated the highest permeability and was selected for further study. Glycylsarcosine (gly-sar, a typical substrate of PepT1) uptake by Caco-2 cells can be inhibited by 2 in a concn.-dependent manner, and IC50 for 2 was 2.18 ± 0.12 mM. The uptake of 2 was markedly increased in the long-term leptin-treated Caco-2 cells compared with the control Caco-2 cells, and was significantly inhibited by the excess of gly-sar, but not by L-valine. A dose-proportional pharmacokinetics was obsd. in rats when 5, 15, 30 mg/kg doses of 2 (calcd. as 1) were orally administered. The oral abs. bioavailability of 1 was 60.0% and 21.8% after 2 and 1 were orally administered to rats 30 mg/kg, resp. Following oral administration of 15 mg/kg, the absorption and bioactivation of 2 were extensive and rapid, over 98% of prodrug hydrolysis occurring before appearance in the portal vein. The in vivo dispositions of 1-β-D-arabinofuranosyluracil (ara-U), a deaminated product of 1, were investigated. Oral administration of 2 resulted in an increased 1/ara-U ratio (2.76) in the blood, much higher than that (1.25) after 1 orally taken. Overall, these results demonstrated that the PepT1-mediated absorption of 2 and the increased metabolic stability resulted in a dramatic increase in the oral bioavailability of 1 in rats and further corroborated the thought that prodrug design strategy targeting intestinal PepT1 was an important and promising strategy to improve oral bioavailability of poorly absorbed drugs.(b) Hamada, A.; Kawaguchi, T.; Nakano, M. Clinical pharmacokinetics of cytarabine formulations. Clin. Pharmacokinet. 2002, 41, 705– 718, DOI: 10.2165/00003088-200241100-00002[Crossref], [PubMed], [CAS], Google Scholar214bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XntFyrurs%253D&md5=095c5a6ccb4f1ae88bac4349f16c792eClinical pharmacokinetics of cytarabine formulationsHamada, Akinobu; Kawaguchi, Takeo; Nakano, MasahiroClinical Pharmacokinetics (2002), 41 (10), 705-718CODEN: CPKNDH; ISSN:0312-5963. (Adis International Ltd.)A review. Cytarabine (cytosine arabinoside, Ara-C) is an effective chemotherapeutic agent for the treatment of acute myelogenous leukemia and lymphocytic leukemias. As cytarabine is an S-phase-specific drug, prolonged exposure of cells to cytotoxic concns. is crit. to achieve max. cytotoxic activity. However, the activity of cytarabine is decreased by its rapid deamination to the biol. inactive metabolite uracil arabinoside. This rapid deamination is the reason for the ongoing search for effective formulations and derivs. of cytarabine that cannot be deaminated and exhibit better pharmacokinetic parameters. Protection of cytarabine from fast degrdn. and elimination has been investigated by encapsulating the drug into pharmaceutically acceptable carriers. Cytarabine derivs. have shown promise in vitro and in animal models. For example, ancitabine (cyclocytidine), enocitabine and cytarabine ocfosfate have been used clin. in Japan. Cytarabine encapsulated into multivesicular liposomes has been approved in several countries for the intrathecal treatment of lymphomatous meningitis. Although many compds. have been investigated, few cytarabine derivs. are currently available for clin. use. Further research is needed to improve the efficacy of cytarabine against hematol. and solid tumors.
- 215Zuckerman, T.; Ram, R.; Akria, L.; Koren-Michowitz, M.; Hoffman, R.; Henig, I.; Lavi, N.; Ofran, Y.; Horowitz, N. A.; Nudelman, O.; Tavor, S.; Yeganeh, S.; Gengrinovitch, S.; Flaishon, L.; Tessler, S.; Ben Yakar, R.; Rowe, J. M. BST-236, a novel cytarabine prodrug for patients with acute leukemia unfit for standard induction: a phase 1/2a study. Blood Adv. 2019, 3, 3740– 3749, DOI: 10.1182/bloodadvances.2019000468[Crossref], [PubMed], [CAS], Google Scholar215https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3MfjsVOrtw%253D%253D&md5=c701f8b6e44cd12bec7040731bb92262BST-236, a novel cytarabine prodrug for patients with acute leukemia unfit for standard induction: a phase 1/2a studyZuckerman Tsila; Hoffman Ron; Henig Israel; Lavi Noa; Ofran Yishai; Horowitz Netanel A; Nudelman Olga; Rowe Jacob M; Zuckerman Tsila; Hoffman Ron; Lavi Noa; Ofran Yishai; Horowitz Netanel A; Rowe Jacob M; Ram Ron; Akria Luiza; Koren-Michowitz Maya; Tavor Sigal; Yeganeh Shay; Gengrinovitch Stela; Flaishon Liat; Tessler Shoshi; Ben Yakar Ruth; Rowe Jacob MBlood advances (2019), 3 (22), 3740-3749 ISSN:.High-dose cytarabine is the backbone of acute myeloid leukemia (AML) treatment. Nevertheless, its use in older patients is considerably limited due to increased toxicity. BST-236 (INN aspacytarabine) is a novel cytarabine prodrug designed to deliver high-dose cytarabine to target cells with reduced systemic exposure to free cytarabine. This phase 1/2a dose-escalation study was designed to evaluate BST-236 safety, pharmacokinetics, and efficacy in older or unfit-for-intensive-therapy patients with acute leukemia. Twenty-six patients, unfit for standard therapy, who were either relapsed/refractory or newly diagnosed, received BST-236 in 6 dose-escalating cohorts (range 0.3 to 6 g/m2 per day). BST-236 was administered intravenously once daily over 60 minutes for 6 consecutive days. The median age was 76.5 (26 to 90), with 84.6% of patients ≥70 years. BST-236 was safe and well tolerated. The maximal tolerated dose was 6 g/m2 per day. Overall response rate was 29.6%. A subgroup analysis of newly diagnosed patients with AML, de novo or secondary to myelodysplastic syndrome, unfit for standard induction (median age 78), demonstrated overall response of 45.5%. The median overall survival was 6.5 months and was not reached in patients achieving complete remission. The findings of this phase 1/2 study suggest that BST-236 safely delivers high and efficacious cytarabine doses to older patients who are unfit for standard induction and lays the foundation for further studies of BST-236 in AML. This trial was registered at www.clinicaltrials.gov as #NCT02544438.
- 216Wright, J. A..; Wilson, D. P..; Fox, J. J. Fluoro sugar analogues of arabinosyl- and xylosylcytosines. J. Med. Chem. 1970, 13, 269– 272, DOI: 10.1021/jm00296a024[ACS Full Text], [CAS], Google Scholar216https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE3cXhtVWjtrY%253D&md5=9b6bf2186d3ba1a1b367b3808d66d5fdNucleosides. LXIV. Fluoro sugar analogs of arabinosyl- and xylosylcytosinesWright, John Arthur; Wilson, Dan Patrick; Fox, Jack J.Journal of Medicinal Chemistry (1970), 13 (2), 269-72CODEN: JMCMAR; ISSN:0022-2623.The syntheses of 1-(3-deoxy-3-fluoro- and -2-deoxy-2-fluoro-β-D-xylofuranosyl)cytosines (I and II) and 1-(2-deoxy-2-fluoro-α-and -β-D-arabinofuranosyl)cytosines (III and IV) from their corresponding suitably protected halogenoses are described. The susceptibility of these cytosine nucleosides (I, II, III) to cytidine deaminase was studied along with the susceptibility of several corresponding fluoro sugar adenine nucleosides to adenosine deaminase. Preliminary studies showed that in L1210 mouse leukemia suspension culture, IV has a growth inhibitory effect comparable with that of Ara-C.
- 217Pankiewicz, K. W. Fluorinated nucleosides. Carbohydr. Res. 2000, 327, 87– 105, DOI: 10.1016/S0008-6215(00)00089-6[Crossref], [PubMed], [CAS], Google Scholar217https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXlsVGrtbk%253D&md5=f0bae4f77a55fa0722e7ee2630f751c0Fluorinated nucleosidesPankiewicz, Krzysztof W.Carbohydrate Research (2000), 327 (1-2), 87-105CODEN: CRBRAT; ISSN:0008-6215. (Elsevier Science Ltd.)A review with 97 refs. covering the synthesis and biol. activity of deoxyfluoro nucleosides.
- 218(a) Hertel, L. W.; Kroin, J. S.; Misner, J. W.; Tustin, J. M. Synthesis of 2-deoxy-2,2-difluoro-d-ribose and 2-deoxy-2,2′-difluoro-d-ribofuranosyl nucleosides. J. Org. Chem. 1988, 53, 2406– 2409, DOI: 10.1021/jo00246a002[ACS Full Text.], [CAS], Google Scholar218ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1cXit1ajsbY%253D&md5=887cab7ff0e05a35d11150ec7c1bfea5Synthesis of 2-deoxy-2,2-difluoro-D-ribose and 2-deoxy-2,2'-difluoro-D-ribofuranosyl nucleosidesHertel, L. W.; Kroin, J. S.; Misner, J. W.; Tustin, J. M.Journal of Organic Chemistry (1988), 53 (11), 2406-9CODEN: JOCEAH; ISSN:0022-3263.A program to synthesize fluorinated D-ribose and fluorinated nucleosides was initiated with hopes of finding compds. of potential value as anticancer and/or antiviral agents. The approach is illustrated by a simple and stereocontrolled synthesis of 2-deoxy-2,2-difluoro-D-ribose (I). This was followed with the synthesis of a series of 1-(2-deoxy-2,2-difluororibofuranosyl)pyrimidine nucleosides. (R)-2,3-O-Isopropylideneglyceraldehyde was coupled with Et bromodifluoroacetate by using Reformatskii conditions to yield the carbon skeleton for the desired carbohydrate. Hydrolytic removal of the blocking groups with concomitant closure gave the γ-lactone II. Redn. to the γ-lactol ultimately yielded I. Functionalization of the difluoro carbohydrate with a leaving group at an anomeric position followed by displacement of the group with various pyrimidine bases yielded 1-(2-deoxy-2,2-difluororibofuranosyl)pyrimidine nucleosides.(b) Hertel, L. W.; Kroin, J. S.; Grossman, C. S.; Grindey, G. B.; Dorr, A. F.; Storiolo, A. M. V.; Plunkett, W.; Gandhi, V.; Huang, P. Synthesis and biological activity of 2′,2′-difluorodeoxycytidine (gemcitabine). ACS Symp. Ser. 1996, 639 (Biomedical Frontiers of Fluorine Chemistry), 265– 278, DOI: 10.1021/bk-1996-0639.ch019[ACS Full Text], [CAS], Google Scholar218bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28Xlsleisrc%253D&md5=d3ec17bff51d1e1bb82c3c68c31c9e46Synthesis and biological activity of 2',2'-difluorodeoxycytidine (gemcitabine)Hertel, L. W.; Kroin, J. S.; Grossman, C. S.; Grindey, Gerald B.; Dorr, A. F.; Storiolo, A. M. V.; Plunkett, W.; Gandhi, V.; Huang, P.ACS Symposium Series (1996), 639 (Biomedical Frontiers of Fluorine Chemistry), 265-278CODEN: ACSMC8; ISSN:0097-6156. (American Chemical Society)GEMZAR (gemcitabine-HCl) is a difluorinated analog of deoxy cytidine. It was initially synthesized as a novel anti-viral compd. with broad spectrum in vitro activity against both RNA and DNA viruses. However, the compd. proved to have a narrow therapeutic index when it was administered daily during the in vivo evaluation of antiviral activity. Using a staggered schedule of administration, GEMZAR was found to be a potent antitumor agent in murine and human xenograft solid tumor models. Studies showed that gemcitabine diphosphate was a ribonucleotide reductase inhibitor, whereas the triphosphate is a potent and unique terminator of DNA synthesis. In phase I studies a variety of dose schedules were investigated. Based on phase I studies including pharmacokinetic data, phase II studies were initiated. Activity was obsd. in a variety of solid tumors. The results were specially encouraging for non-small cell lung and pancreatic cancer. GEMZAR is currently undergoing registration review of the Phase III clin. trials for treatment of non-small cell lung and pancreatic cancer. A symposium report.
- 219(a) Bender, D. M.; Bao, J.; Dantzig, A. H.; Diseroad, W. D.; Law, K. L.; Magnus, N. A.; Peterson, J. A.; Perkins, E. J.; Pu, Y.; Reutzel-Edens, S. M.; Remick, D. M.; Starling, J. J.; Stephenson, G. A.; Vaid, R. K.; Zhang, D.; McCarthy, J. R. Synthesis, crystallization, and biological evaluation of an orally active prodrug of gemcitabine. J. Med. Chem. 2009, 52, 6958– 6961, DOI: 10.1021/jm901181h[ACS Full Text.], [CAS], Google Scholar219ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtlWmu7vJ&md5=447a5e55755846def3cf1eaae05a85b6Synthesis, Crystallization, and Biological Evaluation of an Orally Active Prodrug of GemcitabineBender, David M.; Bao, Jingqi; Dantzig, Anne H.; Diseroad, William D.; Law, Kevin L.; Magnus, Nicholas A.; Peterson, Jeffrey A.; Perkins, Everett J.; Pu, Yangwei J.; Reutzel-Edens, Susan M.; Remick, David M.; Starling, James J.; Stephenson, Gregory A.; Vaid, Radhe K.; Zhang, Deyi; McCarthy, James R.Journal of Medicinal Chemistry (2009), 52 (22), 6958-6961CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The design, synthesis, and biol. characterization of an orally active prodrug I of gemcitabine are described. Addnl., the identification of a novel co-crystal solid form of the compd. is presented. Valproate amide I is orally bio-available and releases gemcitabine into the systemic circulation after passing through the intestinal mucosa. The compd. has entered clin. trials and is being evaluated as a potential new anticancer agent.(b) Pratt, S. E.; Durland-Busbice, S.; Shepard, R. L.; Heinz-Taheny, K.; Iversen, P. W.; Dantzig, A. H. Human carboxylesterase-2 hydrolyzes the prodrug of gemcitabine (LY2334737) and confers prodrug sensitivity to cancer cells. Clin. Cancer Res. 2013, 19, 1159– 1168, DOI: 10.1158/1078-0432.CCR-12-1184[Crossref], [PubMed], [CAS], Google Scholar219bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjsFekt7k%253D&md5=37b16874ce4de70dea8a5e57f8aa8a0bHuman Carboxylesterase-2 Hydrolyzes the Prodrug of Gemcitabine (LY2334737) and Confers Prodrug Sensitivity to Cancer CellsPratt, Susan E.; Durland-Busbice, Sara; Shepard, Robert L.; Heinz-Taheny, Kathleen; Iversen, Philip W.; Dantzig, Anne H.Clinical Cancer Research (2013), 19 (5), 1159-1168CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)Purpose: The oral prodrug of gemcitabine LY2334737 is cleaved systemically to gemcitabine; the mechanism responsible for hydrolysis is unknown. LY2334737 cytotoxicity was tested in the NCI-60 panel; mining of microarray expression data identified carboxylesterase (CES) as a top hydrolase candidate. Studies examd. whether CES is responsible for hydrolysis and whether cellular CES expression confers prodrug sensitivity. Exptl. Design: Human recombinant CES isoenzymes were assayed for LY2334737 hydrolysis. Stable CES-overexpressing HCT-116 transfectants and a SK-OV-3 knockdown were prepd. Cell lines were tested for drug sensitivity and CES expression by quant. real time-PCR (qRT-PCR), Western blotting, and immunohistochem. staining. Bystander cytotoxicity studies were conducted with GFP-tagged PC-3 cells as the reporter cell line. Therapeutic response of the HCT-116 transfectants was evaluated in xenografts. Results: Of 3 human CES isoenzymes tested, only CES2 hydrolyzed LY2334737. Five cell lines that express CES2 responded to LY2334737 treatment. LY2334737 was less cytotoxic to a SK-OV-3 CES2 knockdown than parental cells. The drug response of CES2-transfected HCT-116 cells correlated with CES2 expression level. Bystander studies showed statistically greater PC-3-GFP growth inhibition by LY2334737 when cells were cocultured with CES2 and not mock transfectants. Oral treatment of xenograft models with 3.2 mg/kg LY2334737 once a day for 21 days showed greater tumor growth inhibition of CES2 transfectant than the mock transfectant (P ≤ 0.001). Conclusions: CES2 is responsible for the slow hydrolysis of LY2334737. Because intact prodrug circulates at high plasma levels after oral LY2334737 administration, improved response rates may be obsd. by tailoring LY2334737 treatment to patients with CES2 tumor expression. Clin Cancer Res; 19(5); 1159-68. ©2012 AACR.
- 220(a) Sofia, M. J.; Bao, D.; Chang, W.; Du, J.; Nagarathnam, D.; Rachakonda, S.; Reddy, P. G.; Ross, B. S.; Wang, P.; Zhang, H.; Bansal, S.; Espiritu, C.; Keilman, M.; Lam, H. M.; Steuer, M.; Niu, C.; Otto, M. J.; Furman, P. A. Discovery of a β-d-2′-Deoxy-2′-α-fluoro-2′-β-C-methyluridine nucleotide prodrug (PSI-7977) for the treatment of hepatitis C virus. J. Med. Chem. 2010, 53, 7202– 7218, DOI: 10.1021/jm100863x[ACS Full Text.], [CAS], Google Scholar220ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtFKmtb%252FO&md5=33d371e557e9d70562a326f97798f45cDiscovery of a β-D-2'-Deoxy-2'-α-fluoro-2'-β-C-methyluridine Nucleotide Prodrug (PSI-7977) for the Treatment of Hepatitis C VirusSofia, Michael J.; Bao, Donghui; Chang, Wonsuk; Du, Jinfa; Nagarathnam, Dhanapalan; Rachakonda, Suguna; Reddy, P. Ganapati; Ross, Bruce S.; Wang, Peiyuan; Zhang, Hai-Ren; Bansal, Shalini; Espiritu, Christine; Keilman, Meg; Lam, Angela M.; Steuer, Holly M. Micolochick; Niu, Congrong; Otto, Michael J.; Furman, Phillip A.Journal of Medicinal Chemistry (2010), 53 (19), 7202-7218CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Hepatitis C virus (HCV) is a global health problem requiring novel approaches for effective treatment of this disease. The HCV NS5B polymerase has been demonstrated to be a viable target for the development of HCV therapies. β-D-2'-Deoxy-2'-α-fluoro-2'-β-C-Me nucleosides are selective inhibitors of the HCV NS5B polymerase and have demonstrated potent activity in the clinic. Phosphoramidate prodrugs of the 5'-phosphate deriv. of the β-D-2'-deoxy-2'-α-fluoro-2'-β-C-methyluridine nucleoside were prepd. and showed significant potency in the HCV subgenomic replicon assay (<1 μM) and produced high levels of triphosphate 6 in primary hepatocytes and in the livers of rats, dogs, and monkeys when administered in vivo. The single diastereomer 51 of diastereomeric mixt. 14 was crystd., and an X-ray structure was detd. establishing the phosphoramidate stereochem. as Sp, thus correlating for the first time the stereochem. of a phosphoramidate prodrug with biol. activity. 51 (PSI-7977) was selected as a clin. development candidate.(b) Murakami, E.; Tolstykh, T.; Bao, H.; Niu, C.; Steuer, H. M. M.; Bao, D.; Chang, W.; Espiritu, C.; Bansal, S.; Lam, A. M.; Otto, M. J.; Sofia, M. J.; Furman, P. A. Mechanism of activation of PSI-7851 and its diastereoisomer PSI-7977. J. Biol. Chem. 2010, 285, 34337– 34347, DOI: 10.1074/jbc.M110.161802[Crossref], [PubMed], [CAS], Google Scholar220bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtlGktb7O&md5=28287a5f7547ab85158f594cd5fb1cd0Mechanism of Activation of PSI-7851 and Its Diastereoisomer PSI-7977Murakami, Eisuke; Tolstykh, Tatiana; Bao, Haiying; Niu, Congrong; Steuer, Holly M. Micolochick; Bao, Donghui; Chang, Wonsuk; Espiritu, Christine; Bansal, Shalini; Lam, Angela M.; Otto, Michael J.; Sofia, Michael J.; Furman, Phillip A.Journal of Biological Chemistry (2010), 285 (45), 34337-34347CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)A phosphoramidate prodrug of 2'-deoxy-2'-α-fluoro-β-C-methyluridine-5'-monophosphate, PSI-7851, demonstrates potent anti-hepatitis C virus (HCV) activity both in vitro and in vivo. PSI-7851 is a mixt. of two diastereoisomers, PSI-7976 and PSI-7977, with PSI-7977 being the more active inhibitor of HCV RNA replication in the HCV replicon assay. To inhibit the HCV NS5B RNA-dependent RNA polymerase, PSI-7851 must be metabolized to the active triphosphate form. The first step, hydrolysis of the carboxyl ester by human cathepsin A (CatA) and/or carboxylesterase 1 (CES1), is a stereospecific reaction. Western blot anal. showed that CatA and CES1 are both expressed in primary human hepatocytes. However, expression of CES1 is undetectable in clone A replicon cells. Studies with inhibitors of CatA and/or CES1 indicated that CatA is primarily responsible for hydrolysis of the carboxyl ester in clone A cells, although in primary human hepatocytes, both CatA and CES1 contribute to the hydrolysis. Hydrolysis of the ester is followed by a putative nucleophilic attack on the phosphorus by the carboxyl group resulting in the spontaneous elimination of phenol and the prodn. of an alaninyl phosphate metabolite, PSI-352707, which is common to both isomers. The removal of the amino acid moiety of PSI-352707 is catalyzed by histidine triad nucleotide-binding protein 1 (Hint1) to give the 5'-monophosphate form, PSI-7411. SiRNA-mediated Hint1 knockdown studies further indicate that Hint1 is, at least in part, responsible for converting PSI-352707 to PSI-7411. PSI-7411 is then consecutively phosphorylated to the diphosphate, PSI-7410, and to the active triphosphate metabolite, PSI-7409, by UMP-CMP kinase and nucleoside diphosphate kinase, resp.
- 221(a) Kawaguchi, T.; Fukushima, S.; Ohmura, M.; Mishima, M.; Nakano, M. Enzymatic and chemical stability of 2′,3′-dideoxy-2′,3′-didehydropyrimidine nucleosides: potential anti-acquired immunodeficiency syndrome agents. Chem. Pharm. Bull. 1989, 37, 1944– 1945, DOI: 10.1248/cpb.37.1944[Crossref], [PubMed], [CAS], Google Scholar.221ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1MXls1Sjurk%253D&md5=48e7967314da09dea63cccda454277daEnzymic and chemical stability of 2',3'-dideoxy-2',3'-didehydropyrimidine nucleosides: potential anti-acquired immunodeficiency syndrome agentsKawaguchi, Takeo; Fukushima, Shoji; Ohmura, Masayo; Mishima, Motohiro; Nakano, MasahiroChemical & Pharmaceutical Bulletin (1989), 37 (7), 1944-5CODEN: CPBTAL; ISSN:0009-2363.The enzymic and chem. stability of three 2',3'-dideoxy-2',3'-didehydropyrimidine nucleosides was studied. Chem. degrdn. of the analogs was measured in the pH range of 1.0-9.0. 2',3'-Dideoxy-2',3'-didehydrocytidine (DDCN) degraded rapidly under acidic conditions, but the chem. stability was greater under basic conditions. The chem. degrdn. of 2',3'-dideoxy-2',3'-didehydrouridine (DDUN) and 2',3'-dideoxy-2',3'-didehydrothymidine (DDTN) was not pH dependent and was faster than that of cytarabine. Enzymic degrdn. of DDCN, DDUN, and DDTN was not obsd. in human plasma, though cytarabine was degraded enzymically under the same conditions. DDCN was also not degraded in the presence of mouse kidney cytidine deaminase.(b) Shi, J.; Ray, A. S.; Mathew, J. S.; Anderson, K. S.; Chu, C. K.; Schinazi, R. F. 2,3-Didehydro-2,3-dideoxynucleosides are degraded to furfuryl alcohol under acidic conditions. Bioorg. Med. Chem. Lett. 2004, 14, 2159– 2162, DOI: 10.1016/j.bmcl.2004.02.031[Crossref], [PubMed], [CAS], Google Scholar221bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXjtVehurw%253D&md5=b77e08f102f1bcf8d9c0a7bf22591fac2',3'-Didehydro-2',3'-dideoxynucleosides are degraded to furfuryl alcohol under acidic conditionsShi, Junxing; Ray, Adrian S.; Mathew, Judy S.; Anderson, Karen S.; Chu, Chung K.; Schinazi, Raymond F.Bioorganic & Medicinal Chemistry Letters (2004), 14 (9), 2159-2162CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science B.V.)2',3'-Didehydro-2',3'-dideoxynucleosides are clin. relevant antiviral agents. These nucleosides could be degraded under acidic conditions. Acidic stability studies showed the D4N had the following increasing stability order: D4G < cyclo-D4G ≤ RVT < D4T with half-lives ranging from less than 2 min to 35 days. A concerted A-1 mechanism has been proposed for the acidic cleavage of D4-nucleosides. The cleavage products were characterized as furfuryl alc. and the corresponding nucleobase. Furfuryl alc. is an agent found in many everyday food products. The biol. results demonstrated that furfuryl alc. had neither anti-HIV activity nor cytotoxicity in vitro, suggesting the acid instability of D4-nucleosides is unlikely to have an impact on the toxicity of these nucleoside analogs in humans.
- 222Ray, A. S.; Hernandez-Santiago, B. I.; Mathew, J. S.; Murakami, E.; Bozeman, C.; Xie, M.-Y.; Dutschman, G. E.; Gullen, E.; Yang, Z.; Hurwitz, S.; Cheng, Y.-C.; Chu, C. K.; McClure, H.; Schinazi, R. F.; Anderson, K. S. Mechanism of anti-human immunodeficiency virus activity of β-d-6-cyclopropylamino-2′,3′-didehydro-2′,3′-dideoxyguanosine. Antimicrob. Agents Chemother. 2005, 49, 1994– 2001, DOI: 10.1128/AAC.49.5.1994-2001.2005[Crossref], [PubMed], [CAS], Google Scholar222https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXktFSntbs%253D&md5=2b56f435ca07d9ed9562d8382b01bf98Mechanism of anti-human immunodeficiency virus activity of β-D-6-cyclopropylamino-2',3'-didehydro-2',3'-dideoxyguanosineRay, Adrian S.; Hernandez-Santiago, Brenda I.; Mathew, Judy S.; Murakami, Eisuke; Bozeman, Carey; Xie, Meng-Yu; Dutschman, Ginger E.; Gullen, Elizabeth; Yang, Zhenjun; Hurwitz, Selwyn; Cheng, Yung-Chi; Chu, Chung K.; McClure, Harold; Schinazi, Raymond F.; Anderson, Karen S.Antimicrobial Agents and Chemotherapy (2005), 49 (5), 1994-2001CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)To better understand the importance of the oxygen in the ribose ring of planar unsatd. nucleoside analogs that target human immunodeficiency virus (HIV), a 6-cyclopropyl-substituted prodrug of 2',3'-didehydro-2',3'-dideoxyguanosine (cyclo-d4G) was synthesized, and its cellular metab., antiviral activity, and pharmacokinetic behavior were studied. Cyclo-d4G had selective anti-HIV activity in primary blood mononuclear cells (PBMCs), effectively inhibiting the LAI strain of HIV-1 by 50% at 1.1±0.1 μM while showing 50% inhibition of cell viability at 84.5 μM. The antiviral activity in PBMCs was not markedly affected by mutations of methionine to valine at position 184 or by thymidine-assocd. mutations in the viral reverse transcriptase. Mutations of leucine 74 to valine and of lysine 65 to arginine had mild to moderate resistance (as high as fivefold). Studies to delineate the mechanism of cellular metab. and activation of cyclo-d4G showed reduced potency in inhibiting viral replication in the presence of the adenosine/adenylate deaminase inhibitor 2'-deoxycoformycin, implying that the antiviral activity is due to its metab. to the 2'-dGTP analog d4GTP. Intracellular formation of sugar catabolites illustrates the chem. and potentially enzymic instability of the glycosidic linkage in d4G. Further studies suggest that cyclo-d4G has a novel intracellular phosphorylation pathway. Cyclo-d4G had a lower potential to cause mitochondrial toxicity than 2',3'-dideoxycytidine and 2',3'-didehydro-3'-deoxythymidine in neuronal cells. Also, cyclo-d4G had advantageous synergism with many currently used anti-HIV drugs. Poor oral bioavailability obsd. in rhesus monkeys may be due to the labile glycosidic bond, and special formulation may be necessary for oral delivery.
- 223(a) Rana, K. Z.; Dudley, M. N. Clinical pharmacokinetics of stavudine. Clin. Pharmacokinet. 1997, 33, 276– 284, DOI: 10.2165/00003088-199733040-00003[Crossref], [PubMed], [CAS], Google Scholar.223ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXntVGgtrY%253D&md5=629122c446989a5f7a4147f48ee85905Clinical pharmacokinetics of stavudineRana, Khurram Z.; Dudley, Michael N.Clinical Pharmacokinetics (1997), 33 (4), 276-284CODEN: CPKNDH; ISSN:0312-5963. (Adis)A review with 32 refs. Stavudine (d4T) is a pyrimidine nucleoside analog used in the treatment of human immunodeficiency virus (HIV) infection. It inhibits viral reverse transcriptase as do zidovudine (AZT), didanosine (ddI), zalcitabine (ddC) and lamivudine (3TC), which comprise the family of nucleoside HIV-reverse transcriptase inhibitors. Stavudine is currently approved by the US Food and Drug Administration for the treatment of patients who have become intolerant to or have failed to respond to zidovudine, didanosine or zalcitabine therapy. Oral administration of stavudine results in maximal concns. within 2 h and increases linearly as doses increase. The abs. oral bioavailability is high, approaching 100%. There is evidence to suggest that stavudine does not accumulate in the plasma. It distributes into total body water and appears to enter cells by non-facilitated diffusion. Penetration into the cerebrospinal fluid occurs, as does the transfer of the drug across human placental tissue. Stavudine is cleared quickly by both renal and nonrenal processes. The pharmacokinetic properties of stavudine in children are similar to those of adults. The pharmacokinetic parameters of stavudine were not affected by simultaneous administration of didanosine. It appears that stavudine at doses <2 mg/kg/day is most efficient at increasing CD4+ cell nos. While stavudine is reported to be less cytotoxic than zidovudine, the principal toxicity in humans is peripheral neuropathy and appears to be related to daily, but not cumulative, doses.(b) Becher, F.; Landman, R.; Mboup, S.; Kane, C. N.; Canestri, A.; Liegeois, F.; Vray, M.; Prevot, M. H.; Leleu, G.; Benech, H. Monitoring of didanosine and stavudine intracellular trisphosphorylated anabolite concentrations in HIV-infected patients. AIDS 2004, 18, 181– 187, DOI: 10.1097/00002030-200401230-00006[Crossref], [PubMed], [CAS], Google Scholar223bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXislars7c%253D&md5=b4dabe663adbd1cd65bfbe6c793525f5Monitoring of didanosine and stavudine intracellular trisphosphorylated anabolite concentrations in HIV-infected patientsBecher, Francois; Landman, Roland; Mboup, S.; Kane, C. Ndeye Toure; Canestri, Ana; Liegeois, Florent; Vray, Murielle; Prevot, Marie-Helene; Leleu, Ghislaine; Benech, HenriAIDS (London, United Kingdom) (2004), 18 (2), 181-187CODEN: AIDSET; ISSN:0269-9370. (Lippincott Williams & Wilkins)The purpose of this study was to det. the concns. of intracellular active anabolites of stavudine (d4T) and didanosine (DDI) and their interpatient variability in HIV-infected patients and to explore relationships between plasma and intracellular forms. This pilot study included 28 anti retroviral-naive HIV-infected patients who received d4T (40/30 mg twice daily), ddl (400/250 mg daily) and efavirenz (600 mg daily). After 6 mo of therapy, 7 mL of blood was collected between 0.5 and 16.2 h and 2.5 and 28.5 h after the last dose of d4T and ddl, resp. Plasma samples were obtained for the detn. of d4T and ddl concns. Peripheral blood mononuclear cells were prepd. for measuring intracellular d4T and ddl triphosphates (d4T-TP and ddA-TP, resp.). D4T-TP and ddA-TP concns. were above the limit of quantification in 25 of 26 compliant patients: median d4T-TP was 31 fmol/106 cells (range, 0-99) and median ddA-TP was 8 fmol/106 cells (range, 0-23). The half-life of d4T-TP was calcd. as 7 h. Interpatient variability in d4T-TP and ddA-TP concns. was 48% and 58%, resp. A significant relationship was obsd. between plasma d4T and intracellular d4T-TP. No relation was found between ddl and ddA-TP. A linear relation was obsd. between the intracellular concns. of d4T-TP and ddA-TP. This is the first time that data have been obtained on intracellular concns. of d4T-TP and ddA-TP, their intracellular pharmacokinetics and interpatient variability. Other similar studies with more patients are needed to enhance knowledge of the intracellular pharmacol. of the nucleoside reverse transcriptase inhibitors.
- 224(a) Schaeffer, H. J.; Beauchamp, L.; Miranda, de P.; Elion, G. B.; Bauer, D. J.; Collins, P. 9-(2-Hydroxyethoxymethyl)guanine activity against viruses of the herpes group. Nature 1978, 272, 583– 585, DOI: 10.1038/272583a0[Crossref], [PubMed], [CAS], Google Scholar.224ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE1cXltVSjsr0%253D&md5=383b527f72528e860c4b21f2fdb7fccd9-(2-Hydroxyethoxymethyl)guanine activity against viruses of the herpes groupSchaeffer, H. J.; Beauchamp, Lilia; De Miranda, P.; Elion, Gertrude B.; Bauer, D. J.; Collins, P.Nature (London, United Kingdom) (1978), 272 (5654), 583-5CODEN: NATUAS; ISSN:0028-0836.Of a series of nucleoside analogs synthesized, 9-(2-hydroxyethoxymethyl)guanine (I) [59277-89-3] had marked antiviral activity with low toxicity in animal models of herpes virus infections. In mice the oral and i.p. LD50 values for I were >10,000 and 1000 mg/kg, resp.; no toxicity was obsd. in mice given oral I (450 mg/kg) daily for 30 days. In mice given I, 14C-labeled at the 8-position of the guanine nucleus, 82 and 94% of label was excreted in urine by 4 and 24 h, resp., essentially as unmetabolized I. No appreciable I binding to plasma or tissues was obsd.(b) Faulds, D.; Heel, R. C. Ganciclovir, A review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy in cytomegalovirus infections. Drugs 1990, 39, 597– 638, DOI: 10.2165/00003495-199039040-00008[Crossref], [PubMed], [CAS], Google Scholar224bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3cXksFWqs7g%253D&md5=21f69e930a9cae9afc92f98f615d2b1fGanciclovir: a review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy in cytomegalovirus infectionsFaulds, Diana; Heel, Rennie C.Drugs (1990), 39 (4), 597-638CODEN: DRUGAY; ISSN:0012-6667.A review with 193 refs.
- 225(a) Soul-Lawton, J.; Seaber, E.; On, N.; Wootton, R.; Rolan, P.; Posner, J. Absolute bioavailability and metabolic disposition of valaciclovir, the L-valyl ester of acyclovir, following oral administration to humans. Antimicrob. Agents Chemother. 1995, 39, 2759– 2764, DOI: 10.1128/AAC.39.12.2759[Crossref], [PubMed], [CAS], Google Scholar.225ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXps1Orsbk%253D&md5=bf55e491328feb42e158c4a9626777daAbsolute bioavailability and metabolic disposition of valaciclovir, the L-valyl ester of acyclovir, following oral administration to humansSoul-Lawton, J.; Seaber, E.; On, N.; Wootton, R.; Rolan, P.; Posner, J.Antimicrobial Agents and Chemotherapy (1995), 39 (12), 2759-64CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)Valaciclovir (Valtrex), the L-valyl ester of acyclovir, is undergoing clin. development for the treatment and suppression of herpesviral diseases. The abs. bioavailability of acyclovir from valaciclovir and the metabolic disposition of valaciclovir were investigated with healthy volunteers in two sep. studies. In a randomized, crossover study, 12 fasting healthy volunteers each received 1,000 mg of oral valaciclovir and a 1-h i.v. infusion of 350 mg of acyclovir. The mean abs. bioavailability of acyclovir was 54.2%, a value three to five times that obtained previously with oral acyclovir. A similar est. of 51.3% was made from urinary recovery of acyclovir. In the second study, four fasting volunteers received a single oral dose of 1,000 mg of [14C]valaciclovir. The majority of plasma radioactivity was accounted for by acyclovir, with very low plasma valaciclovir concns. (mean max. concn. of drug in plasma = 0.19 μM0, which were undetectable after 3 h postdose. By 168 h, more than 90% of the administered radioactive dose was recovered, with approx. 46% in urine and 47% in feces. More than 99% of the radioactivity recovered in urine corresponded to acyclovir and its known metabolites, 9-(carboxymethoxymethyl)guainine and 8-hydroxy-9-[(2-hydroxyethoxy)methyl]guanine, with valaciclovir accounting for less than 0.5% of the dose. Acyclovir, but no valaciclovir, was detected in fecal samples. These studies show that after oral administration to humans, valaciclovir is rapidly and virtually completely converted to acyclovir to provide a high level of acyclovir bioavailability in comparison with that following oral administration of acyclovir. The plasma acyclovir exposure obtained following oral administration of valaciclovir is similar to that achieved with doses of i.v. acyclovir, which are effective in the treatment and suppression of the less susceptible herpesviral diseases.(b) Abete, J. F.; Martín-Davila, P.; Moreno, S.; Quijino, Y.; Vicente, E.; Pou, L. Pharmacokinetics of oral valganciclovir and intravenous ganciclovir administered to prevent cytomegalovirus disease in an adult patient receiving small-intestine transplantation. Antimicrob. Agents Chemother. 2004, 48, 2782– 2783, DOI: 10.1128/AAC.48.7.2782-2783.2004[Crossref], [PubMed], [CAS], Google Scholar225bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXlsFWlsr0%253D&md5=e6154602210aa0d5b0b823a133b5a622Pharmacokinetics of oral valganciclovir and intravenous ganciclovir administered to prevent cytomegalovirus disease in an adult patient receiving small-intestine transplantationAbete, Jesus Fortun; Martin-Davila, Pilar; Moreno, S.; Quijano, Yolanda; De Vicente, Emilio; Pou, LeonorAntimicrobial Agents and Chemotherapy (2004), 48 (7), 2782-2783CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)There is no expanded citation for this reference.
- 226(a) de Vrueh, R. L. A.; Smith, P. L.; Lee, C. P. Transport of L-valine-acyclovir via the oligopeptide transporter in the human intestinal cell line, Caco-2. J. Pharmacol. Exp. Ther. 1998, 286, 1166– 1170[PubMed], [CAS], Google Scholar.226ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXmt1Gru70%253D&md5=387fc11bc6d4c9478431e0d3279dd811Transport of L-valine-acyclovir via the oligopeptide transporter in the human intestinal cell line, Caco-2De Vrueh, Remco L. A.; Smith, Philip L.; Lee, Chao-PinJournal of Pharmacology and Experimental Therapeutics (1998), 286 (3), 1166-1170CODEN: JPETAB; ISSN:0022-3565. (Williams & Wilkins)It has been reported that conjugating acyclovir, a potent antiviral with low oral bioavailability, to L-valine increases its urinary excretion in rats. However, it was also reported that this increase is not found for the D-valine ester, suggesting that a carrier-mediated mechanism is involved in its intestinal absorption. Therefore, mechanisms involved in the transepithelial transport of L-valine-acyclovir were investigated using the intestinal cell line, Caco-2, as a model system for the intestinal epithelium. Only the mucosal-to-serosal transport of acyclovir was increased by conjugation with L-valine (∼7-fold), suggesting the involvement of a carrier-mediated mechanism. This conclusion was supported by the finding that this increase was saturable. The mucosal-to-serosal transport of L-valine-acyclovir could be inhibited by L-glycylsarcosine, but not by L-valine, suggesting the involvement of the dipeptide carrier. Also it was found that L-valine-acyclovir inhibits the uptake of cephalexin, a substrate for the oligopeptide transporter. Stability of the esters in either the mucosal or serosal bathing soln. is more than 90% after completion of the transport study. However, after transport, the receiver soln. contained approx. 90% of acyclovir. Based on these findings it was concluded that absorption of the L-valine ester of acyclovir occurs as a result of uptake by the oligopeptide transporter at the apical cell membrane followed by intracellular hydrolysis of the ester and efflux of acyclovir.(b) Han, H. K.; de Vrueh, R. L. A.; Rhie, J. K.; Covitz, K. M. Y.; Smith, P. L.; Lee, C. P.; Oh, D. M.; Sadee, W.; Amidon, G. L. 5′-Amino acid esters of antiviral nucleosides, acyclovir and AZT, are absorbed by the intestinal PEPT1 peptide transporter. Pharm. Res. 1998, 15, 1154– 1159, DOI: 10.1023/A:1011919319810[Crossref], [PubMed], [CAS], Google Scholar.226bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXltFynsb4%253D&md5=b370b141aa1747280d117cf07c51a7b25'-Amino acid esters of antiviral nucleosides, acyclovir, and AZT are absorbed by the intestinal PEPT1 peptide transporterHan, Hyo-Kyung; De Vrueh, Remco L. A.; Rhie, Julie K.; Covitz, Kuang-Ming Y.; Smith, Philip L.; Lee, Chao-Pin; Oh, Doo-Man; Sadee, Wolfgang; Amidon, Gordon L.Pharmaceutical Research (1998), 15 (8), 1154-1159CODEN: PHREEB; ISSN:0724-8741. (Plenum Publishing Corp.)General use of nucleoside analogs in the treatment of viral infections and cancer is often limited by poor oral absorption. Valacyclovir, a water sol. amino acid ester prodrug of acyclovir has been reported to increase the oral bioavailability of acyclovir but its absorption mechanism is unknown. This study characterized the intestinal absorption mechanism of 5'-amino acid ester prodrugs of the antiviral drugs and examd. the potential of amino acid esters as an effective strategy for improving oral drug absorption. Acyclovir (ACV) and Zidovudine (AZT) were selected as the different sugar-modified nucleoside antiviral agents and synthesized to L-valyl esters of ACV and AZT (L-Val-ACV and L-Val-AZT), D-valyl ester of ACV (D-Val-ACV) and glycyl ester of ACV (Gly-ACV). The intestinal absorption mechanism of these 5'-amino acid ester prodrugs was characterized in three different exptl. systems: in situ rat perfusion model, CHO/hPEPT1 cells and Caco-2 cells. Testing 5'-amino acid ester prodrugs of acyclovir and AZT, the authors found that the prodrugs increased the intestinal permeability of the parent nucleoside analog 3-to 10-fold. The dose- dependent permeation enhancement was selective for the L-amino acid esters. Competitive inhibition studies in rats and in CHO cells transfected with the human peptide transporter, hPEPT1, demonstrated that membrane transport of the prodrugs was mediated predominantly by the PEPT1 H+ H+/dipeptide cotransporter even though these prodrugs did not possess a peptide bond. Finally, transport studies in Caco-2 cells confirmed that the 5'-amino acid ester prodrugs enhanced the transcellular transport of the parent drug. This study demonstrates that L-amino acid-nucleoside chimeras can serve as prodrugs to enhance intestinal absorption via the PEPT1 transporter, providing a novel strategy for improving oral therapy of nucleoside drugs.(c) Sugawara, M.; Huang, W.; Fei, Y. J.; Leibach, F. H.; Ganapathy, V.; Ganapathy, M. E. Transport of valganciclovir, a ganciclovir prodrug, via peptide transporters PEPT1 and PEPT2. J. Pharm. Sci. 2000, 89, 781– 789, DOI: 10.1002/(SICI)1520-6017(200006)89:6<781::AID-JPS10>3.0.CO;2-7[Crossref], [PubMed], [CAS], Google Scholar226chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXkt1artbY%253D&md5=bff73ba55562df124b08ecdaebcaa8b6Transport of valganciclovir, a ganciclovir prodrug, via peptide transporters PEPT1 and PEPT2Sugawara, Mitsuru; Huang, Wei; Fei, You-Jun; Leibach, Frederick H.; Ganapathy, Vadivel; Ganapathy, Malliga E.Journal of Pharmaceutical Sciences (2000), 89 (6), 781-789CODEN: JPMSAE; ISSN:0022-3549. (Wiley-Liss, Inc.)In clin. trials, valganciclovir, the valyl ester of ganciclovir, has been shown to enhance the bioavailability of ganciclovir when taken orally by patients with cytomegalovirus infection. We investigated the role of the intestinal peptide transporter PEPT1 in this process by comparing the interaction of ganciclovir and valganciclovir with the transporter in different exptl. systems. We also studied the interaction of these two compds. with the renal peptide transporter PEPT2. In cell culture model systems using Caco-2 cells for PEPT1 and SKPT cells for PEPT2, valganciclovir inhibited glycylsarcosine transport mediated by PEPT1 and PEPT2 with Ki values (inhibition const.) of 1.68 ± 0.30 and 0.043 ± 0.005 mM, resp. The inhibition by valganciclovir was competitive in both cases. Ganciclovir did not interact with either transporter. Similar studies done with cloned PEPT1 and PEPT2 in heterologous expression systems yielded comparable results. The transport of valganciclovir via PEPT1 was investigated directly in PEPT1-expressing Xenopus laevis oocytes with an electrophysiol. approach. Valganciclovir, but not ganciclovir, induced inward currents in PEPT1-expressing oocytes. These results demonstrate that the increased bioavailability of valganciclovir is related to its recognition as a substrate by the intestinal peptide transporter PEPT1. This prodrug is also recognized by the renal peptide transporter PEPT2 with high affinity.
- 227(a) Bonvicini, P.; Levi, A.; Lucchini, V.; Modena, G.; Scorrano, G. Acid-base behavior of alkyl sulfur and oxygen bases. J. Am. Chem. Soc. 1973, 95, 5960– 5964, DOI: 10.1021/ja00799a023[ACS Full Text.], [CAS], Google Scholar227ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE3sXlt1GlsbY%253D&md5=2679544e870e3767b49fb41f537f9e65Acid-base behavior of alkyl sulfur and oxygen basesBonvicini, Piero; Levi, Arrigo; Lucchini, Vittorio; Modena, Giorgio; Scorrano, GianfrancoJournal of the American Chemical Society (1973), 95 (18), 5960-4CODEN: JACSAT; ISSN:0002-7863.The acid-base equilibria in H2SO4 solns. of simple dialkyl ethers were evaluated by a NMR technique and compared with results obtained on corresponding sulfides. The pKBH+ values are ∼4 units more positive for ethers than for sulfides. The reasons of different solvation requirements of weak bases are briefly discussed and related to differences in Bunnett and Olsen .vphi. values. The .vphi. values for ethers (∼+0.8) are much greater than for sulfides (∼-0.3). This makes the ionization ratio of sulfides greater than that of ethers at higher acidities, which is related with the order of basicity obsd. in the gas phase (R2S > R2O). Estimation of the basicity of methyl mercaptan and methyl disulfide suggests the basicity scale R2S > R2S2 ≃ RSH, whereas MeOH is found more basic than Me2O.(b) Fife, T. H.; Jao, L. K. The acid-catalyzed hydrolysis of 2-(substituted phenyl)-1,3-oxathiolanes. J. Am. Chem. Soc. 1969, 91, 4217– 4220, DOI: 10.1021/ja01043a034[ACS Full Text], [CAS], Google Scholar227bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF1MXks1Sgsr0%253D&md5=5267341d3dabc5b3ccebf6b874450f9dAcid-catalyzed hydrolysis of 2-(substituted phenyl)-1,3-oxathiolanesFife, Thomas H.; Jao, L. K.Journal of the American Chemical Society (1969), 91 (15), 4217-20CODEN: JACSAT; ISSN:0002-7863.The rates of acid-catalyzed hydrolysis of a series of 2-(substituted phenyl)-1,3-oxathiolanes were measured in H2O and 50% dioxane-H2O. A plot of the logarithms of the rate consts. vs. σ, the Hammett substituent const., is curved, the point for the p-methoxy-substituted compd. showing considerable pos. deviation from the line established by the use of m-substituted compds. and compds. having electron-withdrawing substituents in the p-position (ρ = -2.8). The p-methoxy group produces neg. deviation when σ+ consts. are employed and H2O is the solvent. Reasonable linearity is obtained, however, with σ+ and the logarithms of rate consts. measured in 50% dioxane-H2O. A plot of log kobsd for hydrolysis of 2-(p-nitrophenyl)-1,3-oxathiolane in various aq. HCl solns. vs. -H0 is linear with a slope of 1.23. Thus, the transition state in these hydrolysis reactions must resemble a carbonium ion with the most likely mechanism involving a unimol. decompn. of a protonated intermediate. The value of kD2O/kH2O for hydrolysis of 2-(p-methoxyphenyl)-1,3-oxathiolane (1.93) is considerably less than normally observed for hydrolysis of analogous acetals and may indicate that the protonated intermediate has S protonated. The value of ΔS* for hydrolysis of 2-phenyl-1,3-oxathiolane is -13.2 entropy units.
- 228Chandrasekhar, S.; Chopra, D.; Gopalaiah, K.; Row, T. The generalized anomeric effect in the 1,3-thiazolidines: Evidence for both sulphur and nitrogen as electron donors. Crystal structures of various N-acylthiazolidines including mercury(II) complexes. Possible relevance to penicillin action. J. Mol. Struct. 2007, 837, 118– 131, DOI: 10.1016/j.molstruc.2006.10.034[Crossref], [CAS], Google Scholar228https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXksVyhs70%253D&md5=d712e761aada8013b860d4f52ae95928The generalized anomeric effect in the 1,3-thiazolidines: Evidence for both sulphur and nitrogen as electron donors. Crystal structures of various N-acylthiazolidines including mercury(II) complexes. Possible relevance to penicillin actionChandrasekhar, Sosale; Chopra, Deepak; Gopalaiah, Kovuru; Guru Row, Tayur N.Journal of Molecular Structure (2007), 837 (1-3), 118-131CODEN: JMOSB4; ISSN:0022-2860. (Elsevier B.V.)Evidence for the generalized anomeric effect (GAE) in the N-acyl-1,3-thiazolidines, an important structural motif in the penicillins, was sought in the crystal structures of N-(4-nitrobenzoyl)-1,3-thiazolidine and its (2:1) complex with mercuric chloride, N-acetyl-2-phenyl-1,3-thiazolidine, and the (2:1) complex of N-benzoyl-1,3-thiazolidine with mercuric bromide. An inverse relationship was generally obsd. between the C2-N and C2-S bond lengths of the thiazolidine ring, supporting the existence of the GAE. (Maximal bond length changes were ∼0.04 Å for C2-N3, S1-C2, and ∼0.08 Å for N3-C6.). Comparison with N-acylpyrrolidines and tetrahydrothiophenes indicates that both the nitrogen-to-sulfur and sulfur-to-nitrogen GAE's operate simultaneously in the 1,3-thiazolidines, the former being dominant. (This is analogous to the normal and exo-anomeric effects in pyranoses, and also leads to an interesting application of Baldwin's rules.). The nitrogen-to-sulfur GAE is generally enhanced in the mercury(II) complexes (presumably via coordination at the sulfur); a competition' between the GAE and the amide resonance of the N-acyl moiety is apparent. There is evidence for a 'push-pull' charge transfer between the thiazolidine moieties in the mercury(II) complexes, and for a 'back-donation' of charge from the bromine atoms to the thiazolidine moieties in the HgBr2 complex. (The sulfur atom appears to be sp2 hybridized in the mercury(II) complexes, possibly for stereoelectronic reasons.). These results are apparently relevant to the mode of action of the penicillins.
- 229Dionne, G. 3TC: a Canadian scientific success story. McGill Journal of Medicine (MJM). 1999, 5, 60– 65
- 230Liotta, D. C.; Painter, G. R. Discovery and development of the anti-human immunodeficiency virus drug, emtricitabine (emtriva, FTC). Acc. Chem. Res. 2016, 49, 2091– 2098, DOI: 10.1021/acs.accounts.6b00274[ACS Full Text], [CAS], Google Scholar230https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhs1SqsrnN&md5=61144ce2d7cc93822a86dc07c0cf8645Discovery and Development of the Anti-Human Immunodeficiency Virus Drug, Emtricitabine (Emtriva, FTC)Liotta, Dennis C.; Painter, George R.Accounts of Chemical Research (2016), 49 (10), 2091-2098CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)The HIV/AIDS epidemic, which was first reported on in 1981, progressed in just ten years to a disease afflicting ten million people worldwide including one million in the US. In 1987 AZT was approved for treating HIV/AIDS. Unfortunately, its clin. usefullness was severly limited by assocd. toxicities and the emergence of resistance. Three other drugs that were approved in the early 1990s suffered from similar liabilities. In 1990 the Liotta group at Emory University developed a highly diastereoselective synthesis of racemic 3'-thia-2',3'-dideoxycytidine and 3'-thia-2',3'-5-fluorodideoxycytidine and demonstrated that these compds. exhibited excellent anti-HIV activity with no apparent cytotoxicity. Subsequently, the enantiomers of these compds. were sepd. using enzyme-mediated kinetic resolns. and their (-)-enantiomers (3TC and FTC, resp.) were found to have exceptionally attractive preclin. profile. In addn. to their anti-HIV activity, 3TC and FTC potently inhibited the replication of hepatitis B virus. The development of FTC, which was being carried out by Burroughs Wellcome, had many remarkable starts and stops. For example, passage studies indicated that the compd. rapidly selected for a single resistant mutant, M184 V, and that this strain was 500-1000 fold less sensitive to FTC than was wild type virus. Fortunately, it was found that combinations of AZT with either 3TC or FTC were synergistic with AZT. The effectiveness of AZT-3TC combination therapy was subsequently demonstrated in four independent clin. trials and in 1997 the FDA approved Combivir, a fixed dose combination of AZT and 3TC. In Phase 1 clin. trials FTC was well tolerated by all subjects with no adverse events obsd. However, the development of FTC was halted by the aquistition of Wellcome PLC by Glaxo PLC in Jan., 1995. In 1996 Triangle Pharmaceuticals licensed FTC from Emory and initiated a series of Phase I/II clin. studies that demonstrated the safety and efficacy of the drug. In August, 1998 FTC was granted "Fast Track" status, based primarily on its potential for once daily dosing. While the outcomes of two subsequent Phase III trials were pos., a third Phase III clin. trial involving combinations of 3TC or FTC with stavudine and neviripine had to be terminated due to serious liver-related adverse events. Although anal. of the data suggested that the liver toxicity was due to neviripine, the FDA decided that the study could not be used for drug registration. Ultimately, in Jan., 2003 Gilead Sciences acquired Triangle Pharmaceuticals and completed the development of FTC (emtricitabine), which was approved for once a day, oral administration in July, 2003. A year later, Truvada, a once a day, oral, fixed dose combination of emtricitabine and tenofovir disoproxyl fumarate received FDA approval and quickly became the accepted first line therapy when used with a third antiretroviral agent. In July, 2006 the FDA approved Atripla, a once a day, oral, fixed dose combination of emtricitabine, tenofovir disoproxyl fumarate and efavirenz, which represented the culmination of two decades of research that had transformed AIDS from a death sentence to a manageable chronic disease.
- 231(a) Gumina, G.; Song, G.; Chu, C. K. L-Nucleosides as chemotherapeutic agents. FEMS Microbiol. Lett. 2001, 202, 9– 15, DOI: 10.1016/S0378-1097(01)00285-3[Crossref], [PubMed], [CAS], Google Scholar.231ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXlvFWlurw%253D&md5=6882b91a21ba60c920b0af1cbeefb5d8L-Nucleosides as chemotherapeutic agentsGumina, G.; Song, G.-Y.; Chu, C. K.FEMS Microbiology Letters (2001), 202 (1), 9-15CODEN: FMLED7; ISSN:0378-1097. (Elsevier Science B.V.)A review with refs. Nucleoside analogs have been the cornerstone of antiviral therapy over the past thirty years and, currently, 16 commonly used antiviral drugs belong to this category. Although for long time it was believed that only D-nucleosides, possessing a 'natural' stereochem., could elicit biol. activity, in the last decade this has been proven not to be true. 3TC, a L-nucleoside analog, is one of the most effective anti-HIV and anti-hepatitis B virus drugs, and nine other L-nucleosides are currently undergoing clin. trials and/or preclin. studies as antiviral or antitumoral agents. This article summarizes some biol. features and the current status of these promising L-nucleoside analogs.(b) Kim, H. O.; Shanmuganatban, K.; Alves, A. J.; Jeong, L. S.; Beacb, J. W.; Schinazi, R. F.; Chang, C.; Cheng, Y.; Chu, C. K. Potent anti-HIV and anti-HBV activities of (−)-L-β-dioxolane-C and (+)-L-β-dioxolane-T and their asymmetric syntheses. Tetrahedron Lett. 1992, 33, 6899– 6902, DOI: 10.1016/S0040-4039(00)60890-0[Crossref], [CAS], Google Scholar231bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3sXmtVSgsg%253D%253D&md5=3a52b8a12f67ab3ee751b0ba1141493ePotent anti-HIV and anti-HBV activities of (-)-L-β-dioxolane-C and (+)-L-β-dioxolane-T and their asymmetric synthesesKim, Hea O.; Shanmuganathan, Kirupathevy; Alves, Antonio J.; Jeong, Lak S.; Beach, J. Warren; Schinazi, Raymond F.; Chang, Chien Neng; Cheng, Yung Chi; Chu, Chung K.Tetrahedron Letters (1992), 33 (46), 6899-902CODEN: TELEAY; ISSN:0040-4039.The asym. syntheses of (+)-L-β-dioxolane-T (I; R = Me, R1 = OH) and (-)-L-β-dioxolane-C (I; R= H, R1 = NH2) were accomplished starting from 1,6-anhydro-L-β-gulopyranose (II), and their anti-HIV and anti-HBV activities were evaluated in human PBM cells, CEM cells and 2.2.15 cells, resp.
- 232(a) Grove, K. L.; Guo, X.; Liu, S.-H.; Gao, Z.; Chu, C. K.; Cheng, Y.-C. Anticancer activity of β-l-dioxolane-cytidine, a novel nucleoside analogue with the unnatural L configuration. Cancer Res. 1995, 55, 3008– 3011[PubMed], [CAS], Google Scholar.232ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXmvVyitr0%253D&md5=af0bf83131a7ce02e0579e7209de92d5Anticancer activity of β-L-dioxolane-cytidine, a novel nucleoside analog with the unnatural L configurationGrove, Kristie L.; Guo, Xin; Liu, Shwu-Huey; Gao, Zhiling; Chu, Chung K.; Cheng, Yung-ChiCancer Research (1995), 55 (14), 3008-11CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)Naturally occurring nucleosides and all anticancer nucleoside analog drugs are in the β-D-configuration. L-(-)-Dioxolane-cytidine [(-)-OddC] is the first L-nucleotide analog ever shown to have anticancer activity. This compd. was converted within cells to its mono-, di-, and triphosphatate metabolites and was incorporated into DNA. As with cytosine arabinoside, conversion to the monophosphate was catalyzed by cellular deoxycytidine kinase, which was essential for cytotoxicity. However, unlike cytosine arabinoside, (-)-OddC was not susceptible to degrdn. by deoxycytidine deaminase. Because (-)-OddC inhibited the growth of hepatocellular and prostate tumors that are generally difficult to treat, it is a promising candidate for addnl. testing. Our results indicate that there is a great deal of variability in the chiral specificities of cellular enzymes and demonstrate how these differences can be exploited in the design of better anti-viral and anticancer drugs.(b) Lapointe, R.; Letourneau, R.; Steward, W.; Hawkins, R. E.; Batist, G.; Vincent, M.; Whittom, R.; Eatock, M.; Jolivet, J.; Moore, M. Phase II study of troxacitabine in chemotherapy-naïve patients with advanced cancer of the pancreas. Annals Oncol. 2005, 16, 289– 293, DOI: 10.1093/annonc/mdi061[Crossref], [PubMed], [CAS], Google Scholar.232bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2M%252FjvFyhsQ%253D%253D&md5=4d7e4af461cc462cb7977cdda1bc9b3aPhase II study of troxacitabine in chemotherapy-naive patients with advanced cancer of the pancreas: gastrointestinal tumorsLapointe R; Letourneau R; Steward W; Hawkins R E; Batist G; Vincent M; Whittom R; Eatock M; Jolivet J; Moore MAnnals of oncology : official journal of the European Society for Medical Oncology (2005), 16 (2), 289-93 ISSN:0923-7534.BACKGROUND: Troxacitabine (Troxatyl) is a novel L-enantiomer nucleoside analog with activity in pancreatic cancer xenograft models. PATIENTS AND METHODS: Troxacitabine 1.5 mg/m(2) was administered by 30-min infusions daily x5 every 4 weeks to 54 patients with advanced pancreatic cancer. Patients were evaluated for objective tumor response, time to tumor progression (TTP), changes in tumor marker CA 19-9, survival, safety, pain, analgesic consumption, Karnofsky performance status and weight change. RESULTS: Median TTP was 3.5 months (95% CI 2.0-3.8), median survival 5.6 months (95% CI 4.9-7.4), and the 1 year survival rate 19%. Best responses were stable disease in 24 patients with eight patients having stable disease for at least 6 months (15%). A 50% or greater decrease in CA 19-9 was seen in seven of 44 assessed patients (16%). Grade 3 and 4 neutropenia were observed in 37% and 30% of patients with one episode of febrile neutropenia. The most common drug-related non-hematological toxic effects reported were cutaneous, with 22% and 6% of patients reporting grade 2 and 3 skin rash, respectively and 4% grade 2 hand-foot syndrome. CONCLUSION: Troxacitabine administered by a bolus daily x5 monthly regimen has modest activity in advanced pancreatic adenocarcinoma.(c) Moore, L. E.; Boudinot, F. D.; Chu, C. K. Preclinical pharmacokinetics of β-L-dioxolane-cytidine, a novel anticancer agent, in rats. Cancer Chemother. Pharmacol. 1997, 39, 532– 536, DOI: 10.1007/s002800050609[Crossref], [PubMed], [CAS], Google Scholar.232chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXis1ajt74%253D&md5=f375e2216ad2f285caac69f120157705Preclinical pharmacokinetics of β-L-dioxolane-cytidine, a novel anticancer agent, in ratsMoore, Laura E.; Boudinot, F. Douglas; Chu, Chung K.Cancer Chemotherapy and Pharmacology (1997), 39 (6), 532-536CODEN: CCPHDZ; ISSN:0344-5704. (Springer)Following i.v. administration, the plasma concns. of β-L-dioxolane-cytidine (OddC) declined in a biexponential manner with a terminal phase half-life of 1.65 h. Total, renal, and nonrenal clearances were 1.38, 0.30 and 1.08 1/h per kg, resp. Nonrenal clearance was the predominant route of elimination of OddC because 22% of the administered dose was excreted unchanged in the urine. The steady-state vol. of distribution averaged 1.42 l/kg. The nucleoside analog was slowly absorbed after oral administration and bioavailability varied. The pharmacokinetics of OddC in rats were linear over the dose range studied.(d) Swords, R.; Giles, F. Troxacitabine in acute leukemia. Hematology 2007, 12, 219– 227, DOI: 10.1080/10245330701406881[Crossref], [PubMed], [CAS], Google Scholar232dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXmt1ans70%253D&md5=8a51b2b084e37c7500b5568973f5c3d5Troxacitabine in acute leukemiaSwords, R.; Giles, F.Hematology (London, United Kingdom) (2007), 12 (3), 219-227CODEN: HMATFL; ISSN:1024-5332. (Informa Healthcare)A review. Troxacitabine (Troxatyl; BCH-4556; (-)-2'-deoxy-3'-oxacytadine) is the first synthetic L-nucleoside enantiomer to demonstrate broad spectrum cytotoxic activity. It was obtained by exchanging the sulfur endocyclic atom with oxygen in the structure of lamivudine, following the discovery that this agent had cytotoxic, as well as anti-viral activity. The unique "unnatural" stereochem. of troxacitabine has produced impressive cytotoxic potency against a wide range of malignancies in the lab. which led to its selection for clin. development. The initial trials with troxacitabine have established its efficacy in both solid and haematol. malignancies, including those resistant to ara-C (cytarabine). This review will consider troxacitabine in terms of its pharmacol., mode of action, pharmacokinetics, tolerability and clin. efficacy.
- 233Lin, J.; Kira, T.; Gullen, E.; Choi, Y.; Qu, F.; Chu, C. K.; Cheng, Y. Structure-activity relationships of L-dioxolane uracil nucleosides as anti-Epstein Barr virus agents. J. Med. Chem. 1999, 42, 2212– 2217, DOI: 10.1021/jm9806749[ACS Full Text], [CAS], Google Scholar233https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXjt1aqsrc%253D&md5=11f185e3b77be0c05d322c689edcee7bStructure-Activity Relationships of L-Dioxolane Uracil Nucleosides as Anti-Epstein Barr Virus AgentsLin, Ju-Sheng; Kira, Toshihiko; Gullen, Elizabeth; Choi, Yongseok; Qu, Fucheng; Chu, Chung K.; Cheng, Yung-ChiJournal of Medicinal Chemistry (1999), 42 (12), 2212-2217CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A series of 1,3-dioxolanyluracil analogs was prepd. from the dioxolane intermediates and their anti-Epstein Barr virus (anti-EBV) activities were detd. The potency of L-dioxolane uracil nucleosides against EBV replication is dependent on the substituents at the 5-position in the following decreasing order: I > Br > Cl > CH3 > CF3 > F. The most active and selective analog was the iodo deriv. (L-I-OddU) with an EC50 value of 0.03 μM and an EC90 value of 0.16 μM. There was no cytotoxicity or depletion of mitochondrial DNA in cells after exposure to L-I-OddU at 50 μM. The action against EBV replication in H1 cells is time-dependent, and EBV DNA in cells treated with L-I-OddU could rebound to pretreatment levels once the drug was removed. In view of the potent antiviral activity plus favorable toxicity profiles, L-I-OddU may be potentially useful for the treatment of EBV-related infectious diseases as well as for delaying the onset or decreasing the incidence of EBV-assocd. cancers.
- 234Liang, C.; Lee, D. W.; Newton, M. G.; Chu, C. K. Synthesis of L-dioxolane nucleosides and related chemistry. J. Org. Chem. 1995, 60, 1546– 1553, DOI: 10.1021/jo00111a012[ACS Full Text], [CAS], Google Scholar234https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXktlemu78%253D&md5=8dd8cfd960a6749fba35492429e955acSynthesis of L-Dioxolane Nucleosides and Related ChemistryLiang, Chengyi; Lee, Doo Won; Newton, M. Gary; Chu, Chung K.Journal of Organic Chemistry (1995), 60 (6), 1546-53CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)Hydroxymethyldioxolanylfluorouracil I and other novel classes of 1,3-dioxolane nucleosides have been synthesized. Coupling of 2-methoxy-4-[[(tert-butyldiphenylsilyl)oxy]methyl]-1,3-dioxolane (23) or 2-methyl-1,3-dioxolane (9) with silylated 5-fluorouracil, thymine, cytosine, and 5-chlorocytosine in the presence of TMSOTf gave the corresponding 1,3-dioxolane nucleosides. These nucleosides were decompd. and rearranged to the ring-opened products in certain reaction conditions. It was found that 5-fluorouracil nucleosides (12 and 25) were relatively more stable than the thymine or cytosine derivs. (10, 13, and 16). Bulky protecting group (TBDPS) at the 1,3-dioxolane moiety in compd. 24 may also contribute the stability to the 1,3-dioxolane nucleosides. The structures of these novel 1,3-dioxolane nucleosides and ring-opened products have been assigned by NMR spectra, and the mechanisms of decompn. and rearrangement to the ring opened products were discussed.
- 235(a) Goodwin, N. C.; Mabon, R.; Harrison, B. A.; Shadoan, M. K.; Almstead, Z. Y.; Xie, Y.; Healy, J.; Buhring, L. M.; DaCosta, C. M.; Bardenhagen, J.; Mseeh, F.; Liu, Q.; Nouraldeen, A.; Wilson, A. G.; Kimball, D.; Powell, D. R.; Rawlins, D. B. Novel L-xylose derivatives as selective sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors for the treatment of type 2 diabetes. J. Med. Chem. 2009, 52, 6201– 6204, DOI: 10.1021/jm900951n[ACS Full Text.], [CAS], Google Scholar235ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtF2ltb3O&md5=120dfc29a33db5857cb6876b35b9edf4Novel L-Xylose Derivatives as Selective Sodium-Dependent Glucose Cotransporter 2 (SGLT2) Inhibitors for the Treatment of Type 2 DiabetesGoodwin, Nicole C.; Mabon, Ross; Harrison, Bryce A.; Shadoan, Melanie K.; Almstead, Zheng Y.; Xie, Yiling; Healy, Jason; Buhring, Lindsey M.; DaCosta, Christopher M.; Bardenhagen, Jennifer; Mseeh, Faika; Liu, Qingyun; Nouraldeen, Amr; Wilson, Alan G. E.; Kimball, S. David; Powell, David R.; Rawlins, David B.Journal of Medicinal Chemistry (2009), 52 (20), 6201-6204CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The prevalence of diabetes throughout the world continues to increase and has become a major health issue. Recently there have been several reports of inhibitors directed toward the sodium-dependent glucose cotransporter 2 (SGLT2) as a method of maintaining glucose homeostasis in diabetic patients. Herein we report the discovery of the novel O-xyloside 7c (I) that inhibits SGLT2 in vitro and urinary glucose reabsorption in vivo.(b) Goodwin, N. C.; Ding, Z.; Harrison, B. A.; Strobel, E. D.; Harris, A. L.; Smith, M.; Thompson, A. Y.; Xiong, W.; Mseeh, F.; Bruce, D. J.; Diaz, D.; Gopinathan, S.; Li, L.; O’Neill, E.; Thiel, M.; Wilson, A. G.; Carson, K. G.; Powell, D. R.; Rawlins, D. B. Discovery of LX2761, a sodium-dependent glucose cotransporter 1 (SGLT1) inhibitor restricted to the intestinal lumen, for the treatment of diabetes. J. Med. Chem. 2017, 60, 710– 721, DOI: 10.1021/acs.jmedchem.6b01541[ACS Full Text], [CAS], Google Scholar235bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXis1yqtA%253D%253D&md5=d07c28561e0bb9be4320391a94020d5cDiscovery of LX2761, a Sodium-Dependent Glucose Cotransporter 1 (SGLT1) Inhibitor Restricted to the Intestinal Lumen, for the Treatment of DiabetesGoodwin, Nicole C.; Ding, Zhi-Ming; Harrison, Bryce A.; Strobel, Eric D.; Harris, Angela L.; Smith, Melinda; Thompson, Andrea Y.; Xiong, Wendy; Mseeh, Faika; Bruce, Debra J.; Diaz, Damaris; Gopinathan, Suma; Li, Ling; O'Neill, Emily; Thiel, Mary; Wilson, Alan G. E.; Carson, Kenneth G.; Powell, David R.; Rawlins, David B.Journal of Medicinal Chemistry (2017), 60 (2), 710-721CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The increasing no. of people afflicted with diabetes throughout the world is a major health issue. Inhibitors of the sodium-dependent glucose cotransporters (SGLT) have appeared as viable therapeutics to control blood glucose levels in diabetic patients. Herein the authors report the discovery of LX2761, a locally-acting SGLT1 inhibitor that is highly potent in vitro and delays intestinal glucose absorption in vivo to improve glycemic control.
- 236Fioretto, P.; Zambon, A.; Rossato, M.; Busetto, L.; Vettor, R. SGLT2 inhibitors and the diabetic kidney. Diabetes Care 2016, 39, S165– S171, DOI: 10.2337/dcS15-3006[Crossref], [PubMed], [CAS], Google Scholar236https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsFeltLvJ&md5=0be3a707129e0c3fec0f6950b0ad28beSGLT2 inhibitors and the diabetic kidneyFioretto, Paola; Zambon, Alberto; Rossato, Marco; Busetto, Luca; Vettor, RobertoDiabetes Care (2016), 39 (Suppl. 2), S165-S171CODEN: DICAD2; ISSN:0149-5992. (American Diabetes Association, Inc.)Diabetic nephropathy (DN) is the most common cause of end-stage renal disease worldwide. Blood glucose and blood pressure control reduce the risk of developing this complication; however, once DN is established, it is only possible to slow progression. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, the most recent glucose-lowering oral agents, may have the potential to exert nephroprotection not only through improving glycemic control but also through glucose-independent effects, such as blood pressure-lowering and direct renal effects. It is important to consider, however, that in patients with impaired renal function, given their mode of action, SGLT2 inhibitors are less effective in lowering blood glucose. In patients with high cardiovascular risk, the SGLT2 inhibitor empagliflozin lowered the rate of cardiovascular events, esp. cardiovascular death, and substantially reduced important renal outcomes. Such benefits on DN could derive from effects beyond glycemia. Glomerular hyperfiltration is a potential risk factor for DN. In addn. to the activation of the renin-angiotensin-aldosterone system, renal tubular factors, including SGLT2, contribute to glomerular hyperfiltration in diabetes. SGLT2 inhibitors reduce sodium reabsorption in the proximal tubule, causing, through tubuloglomerular feedback, afferent arteriole vasoconstriction and redn. in hyperfiltration. Exptl. studies showed that SGLT2 inhibitors reduced hyperfiltration and decreased inflammatory and fibrotic responses of proximal tubular cells. SGLT2 inhibitors reduced glomerular hyperfiltration in patients with type 1 diabetes, and in patients with type 2 diabetes, they caused transient acute redns. in glomerular filtration rate, followed by a progressive recovery and stabilization of renal function. Interestingly, recent studies consistently demonstrated a redn. in albuminuria. Although these data are promising, only dedicated renal outcome trials will clarify whether SGLT2 inhibitors, in addn. to their glycemic and blood pressure benefits, may provide nephroprotective effects.
- 237(a) Selnick, H. G.; Hess, J. F.; Tang, C.; Liu, K.; Schachter, J. B.; Ballard, J. E.; Marcus, J.; Klein, D. J.; Wang, X.; Pearson, M.; Savage, M. J.; Kaul, R.; Li, T.-S.; Vocadlo, D. J.; Zhou, Y.; Zhu, Y.; Mu, C.; Wang, Y.; Wei, Z.; Bai, C.; Duffy, J. L.; McEachern, E. J. Discovery of MK-8719, a potent O-GlcNAcase inhibitor as a potential treatment for tauopathies. J. Med. Chem. 2019, 62, 10062– 10097, DOI: 10.1021/acs.jmedchem.9b01090[ACS Full Text.], [CAS], Google Scholar237ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhslWms73F&md5=79e26635e124c90c86d4c1beb8b63e23Discovery of MK-8719, a potent O-GlcNAcase inhibitor as a potential treatment for tauopathiesSelnick, Harold G.; Hess, J. Fred; Tang, Cuyue; Liu, Kun; Schachter, Joel B.; Ballard, Jeanine E.; Marcus, Jacob; Klein, Daniel J.; Wang, Xiaohai; Pearson, Michelle; Savage, Mary J.; Kaul, Ramesh; Li, Tong-Shuang; Vocadlo, David J.; Zhou, Yuanxi; Zhu, Yongbao; Mu, Changwei; Wang, Yaode; Wei, Zhongyong; Bai, Chang; Duffy, Joseph L.; McEachern, Ernest J.Journal of Medicinal Chemistry (2019), 62 (22), 10062-10097CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Inhibition of O-GlcNAcase (OGA) has emerged as a promising therapeutic approach to treat tau pathol. in neurodegenerative diseases such as Alzheimer's disease and progressive supranuclear palsy. Beginning with carbohydrate-based lead mols., we pursued an optimization strategy of reducing polar surface area to align the desired drug-like properties of potency, selectivity, high central nervous system (CNS) exposure, metabolic stability, favorable pharmacokinetics, and robust in vivo pharmacodynamic response. Herein, we describe the medicinal chem. and pharmacol. studies that led to the identification of (3aR,5S,6S,7R,7aR)-5-(difluoromethyl)-2-(ethylamino)-3a,6,7,7a-tetrahydro-5H-pyrano[3,2-d]thiazole-6,7-diol 42 (MK-8719), a highly potent and selective OGA inhibitor with excellent CNS penetration that has been advanced to first-in-human phase I clin. trials.(b) Wang, X.; Li, W.; Marcus, J.; Pearson, M.; Song, L.; Smith, K.; Terracina, G.; Lee, J.; Hong, K. K.; Lu, S. X.; Hyde, L.; Chen, S. C.; Kinsley, D.; Melchor, J. P.; Rubins, D. J.; Meng, X.; Hostetler, E.; Sur, C.; Zhang, L.; Schachter, J. B.; Hess, J. F.; Senick, H. G.; Vocadlo, D. J.; McEachern, E. J.; Uslaner, J. M.; Duffy, J. L.; Smith, S. M. MK-8719, a novel and selective O-GlcNAcase inhibitor that reduces the formation of pathological tau and ameliorates neurodegeneration in a mouse model of tauopathy. J. Pharmacol. Exp. Ther. 2020, 374, 252– 263, DOI: 10.1124/jpet.120.266122[Crossref], [PubMed], [CAS], Google Scholar237bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhs1ant7rO&md5=6bc4d898d769945b29816591605d7f91MK-8719, a novel and selective O-GlcNAcase inhibitor that reduces the formation of pathological tau and ameliorates neurodegeneration in a mouse model of tauopathyWang, Xiaohai; Li, Wenping; Marcus, Jacob; Pearson, Michelle; Song, Lixin; Smith, Karen; Terracina, Giuseppe; Lee, Julie; Hong, Kwok-Lam Karen; Lu, Sherry X.; Hyde, Lynn; Chen, Shu-Cheng; Kinsley, David; Melchor, Jerry P.; Rubins, Daniel J.; Meng, Xiangjun; Hostetler, Eric; Sur, Cyrille; Zhang, Lili; Schachter, Joel B.; Hess, J. Fred; Selnick, Harold G.; Vocadlo, David J.; McEachern, Ernest J.; Uslaner, Jason M.; Duffy, Joseph L.; Smith, Sean M.Journal of Pharmacology and Experimental Therapeutics (2020), 374 (2), 252-263CODEN: JPETAB; ISSN:1521-0103. (American Society for Pharmacology and Experimental Therapeutics)Deposition of hyperphosphorylated and aggregated tau protein in the central nervous system is characteristic of Alzheimer disease and other tauopathies. Tau is subject to O-linked N-acetylglucosamine (O-GlcNAc) modification, and O-GlcNAcylation of tau has been shown to influence tau phosphorylation and aggregation. Inhibition of O-GlcNAcase (OGA), the enzyme that removes O-GlcNAc moieties, is a novel strategy to attenuate the formation of pathol. tau. Here we described the in vitro and in vivo pharmacol. properties of a novel and selective OGA inhibitor, MK-8719. In vitro, this compd. is a potent inhibitor of the human OGA enzyme with comparable activity against the corresponding enzymes from mouse, rat, and dog. In vivo, oral administration of MK-8719 elevates brain and peripheral blood mononuclear cell O-GlcNAc levels in a dose-dependent manner. In addn., positron emission tomog. imaging studies demonstrate robust target engagement of MK-8719 in the brains of rats and rTg4510 mice. In the rTg4510 mouse model of human tauopathy, MK-8719 significantly increases brain O-GlcNAc levels and reduces pathol. tau. The redn. in tau pathol. in rTg4510 mice is accompanied by attenuation of brain atrophy, including redn. of forebrain vol. loss as revealed by volumetric magnetic resonance imaging anal. These findings suggest that OGA inhibition may reduce tau pathol. in tauopathies. However, since hundreds of O-GlcNAcylated proteins may be influenced by OGA inhibition, it will be crit. to understand the physiol. and toxicol. consequences of chronic O-GlcNAc elevation in vivo.
- 238Passioura, T.; Watashi, K.; Fukano, K.; Shimura, S.; Saso, W.; Morishita, R.; Ogasawara, Y.; Tanaka, Y.; Mizokami, M.; Sureau, C.; Suga, H.; Wakita, T. De novo macrocyclic peptide inhibitors of hepatitis B virus cellular entry. Cell Chem. Biol. 2018, 25, 906– 915, DOI: 10.1016/j.chembiol.2018.04.011[Crossref], [PubMed], [CAS], Google Scholar238https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXpvVemsL4%253D&md5=abb5f4c3bae8a692b7153546e520f218De Novo Macrocyclic Peptide Inhibitors of Hepatitis B Virus Cellular EntryPassioura, Toby; Watashi, Koichi; Fukano, Kento; Shimura, Satomi; Saso, Wakana; Morishita, Ryo; Ogasawara, Yuki; Tanaka, Yasuhito; Mizokami, Masashi; Sureau, Camille; Suga, Hiroaki; Wakita, TakajiCell Chemical Biology (2018), 25 (7), 906-915.e5CODEN: CCBEBM; ISSN:2451-9448. (Cell Press)Hepatitis B virus (HBV) constitutes a significant public health burden, and currently available treatment options are not generally curative, necessitating the development of new therapeutics. Here we have applied random non-std. peptide integrated discovery (RaPID) screening to identify small macrocyclic peptide inhibitors of HBV entry that target the cell-surface receptor for HBV, sodium taurocholate cotransporting polypeptide (NTCP). In addn. to their anti-HBV activity, these mols. also inhibit cellular entry by the related hepatitis D virus (HDV), and are active against diverse strains of HBV (including clin. relevant nucleos(t)ide analog-resistant and vaccine escaping strains). Importantly, these macrocyclic peptides, in contrast to other NTCP-binding HBV entry inhibitors, exhibited no inhibition of NTCP-mediated bile acid uptake, making them appealing candidates for therapeutic development.
- 239Liu, Y.; Ruan, H.; Li, Y.; Sun, G.; Liu, X.; He, W.; Mao, F.; He, M.; Yan, L.; Zhong, G.; Yan, H.; Li, W.; Zhang, Z. Potent and specific inhibition of NTCP-mediated HBV/HDV infection and substrate transporting by a novel, oral-available cyclosporine a analogue. J. Med. Chem. 2021, 64, 543– 565, DOI: 10.1021/acs.jmedchem.0c01484[ACS Full Text], [CAS], Google Scholar239https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXislShsrzE&md5=d482e6421e8673bab71f255138cdc3fcPotent and Specific Inhibition of NTCP-Mediated HBV/HDV Infection and Substrate Transporting by a Novel, Oral-Available Cyclosporine A AnalogueLiu, Yang; Ruan, Hanying; Li, Ying; Sun, Guoliang; Liu, Xiao; He, Wenhui; Mao, Fengfeng; He, Miaomiao; Yan, Liwei; Zhong, Guocai; Yan, Huan; Li, Wenhui; Zhang, ZhiyuanJournal of Medicinal Chemistry (2021), 64 (1), 543-565CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Analogs of the natural product cyclosporine A (CsA) were developed and assessed as antivirals against infection of hepatitis B virus (HBV) and its satellite hepatitis D virus (HDV). An analog termed 27A exhibits potent inhibition of HBV/HDV infection by specifically blocking viral engagement to its cellular receptor NTCP, while it lacks immunosuppressive activity found in natural CsA. I.p. injection or oral intake of 27A protects HDV-susceptible mouse model from HDV infection. 27A serves as a promising lead for the development of novel anti-HDV/HBV agents.
- 240(a) Satchell, D. P. N.; Satchell, R. S. Mechanisms of hydrolysis of thioacetals. Chem. Soc. Rev. 1990, 19, 55– 81, DOI: 10.1039/cs9901900055[Crossref], [CAS], Google Scholar.240ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3cXkslOgtr4%253D&md5=49ba4e9e2bbc2532f12ca6a4693fc4f1Mechanisms of hydrolysis of thioacetalsSatchell, Derek P. N.; Satchell, Rosemary S.Chemical Society Reviews (1990), 19 (1), 55-81CODEN: CSRVBR; ISSN:0306-0012.This review classifies acetals as either O,O-, O,S-, or S,S compds., and uses the name acetal to subsume ketals; 62 refs.(b) Ali, M.; Satchell, D. P. N. Kinetics and mechanism of hydrolysis of open-chain thioacetals derived from benzophenone and the reactivity of α-thiophenyl carbocations. J. Chem. Soc., Perkin Trans. 2 1995, 167– 170, DOI: 10.1039/P29950000167[Crossref], [CAS], Google Scholar240bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXjtFCqt70%253D&md5=eef4999fe54702f9e1e131515bde9ec4Kinetics and mechanism of hydrolysis of open-chain thioacetals derived from benzophenone and the reactivity of α-thiophenyl carbocationsAli, Muhammad; Satchell, Derek P. N.Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1995), (1), 167-70CODEN: JCPKBH; ISSN:0300-9580. (Royal Society of Chemistry)In a 40% (vol./vol.) dioxane-water solvent, in the presence of 0.3-4.0 mol dm-3 perchloric acid, the rates of hydrolysis of di-Et and di-Ph thioacetals derived from substituted benzophenones exhibit substituent effects, acidity dependencies, activation parameters and solvent isotope effects which all suggest that the hydrolyses follow the A1 mechanism. The di-Et thioacetals are ca. 104-fold less reactive than their O,O-analogs and ca. 104-fold more reactive than the corresponding dithanes, for both of which classes of acetal the ASE2 mechanism of hydrolysis has been suggested. In concd. aq. perchloric acid the diaryl thioacetals are, like the di-Et compds., rapidly and quant. converted into the corresponding α-thio carbocations, which then undergo slow hydrolysis to the benzophenone. Kinetic measurements show that the α-thiophenyl carbocation Ph2C+-SPh is ca. 20-fold more reactive towards hydrolysis than is Ph2C+-SEt, but that substituents in the thiophenyl group have little effect on reactivity (ρ ≃ 0.6). The detailed kinetic results are compatible with our previous suggestions about the mechanism of hydrolysis of α-thio carbocations.
- 241Burghardt, T. E. Developments in the deprotection of thioacetals. J. Sulfur Chem. 2005, 26, 411– 427, DOI: 10.1080/17415990500195198[Crossref], [CAS], Google Scholar241https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XkvFygtw%253D%253D&md5=d74a20de8f93b527e67b7b9be0ce771dDevelopments in the deprotection of thioacetalsBurghardt, T. E.Journal of Sulfur Chemistry (2005), 26 (4-5), 411-427CODEN: JSCOFC; ISSN:1741-5993. (Taylor & Francis Ltd.)A review. Dithioacetals are very important and commonly used protecting groups for carbonyl compds. Among the advantages of their use are the ease of formation, stability under both acidic and basic conditions, and umpolung reactivity. Unfortunately, their deprotection into the corresponding carbonyls is quite often difficult and requires special conditions. Hence, numerous protocols for the dithiane deprotection were devised. In this review, various methodologies that were developed for the hydrolysis of thioacetal protecting groups are summarized and the detailed reaction conditions are presented.
- 242Cushman, D. W.; Ondetti, M. A. Personal and historical perspectives. History of the design of captopril and related inhibitors of angiotensin converting enzyme. Hypertension 1991, 17, 589– 592, DOI: 10.1161/01.HYP.17.4.589[Crossref], [PubMed], [CAS], Google Scholar242https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK3M7pt12jtg%253D%253D&md5=f58df34650d294b90336cef9fb37d76dHistory of the design of captopril and related inhibitors of angiotensin converting enzymeCushman D W; Ondetti M AHypertension (Dallas, Tex. : 1979) (1991), 17 (4), 589-92 ISSN:0194-911X.There is no expanded citation for this reference.
- 243Patchett, A. A. Excursions in drug discovery. J. Med. Chem. 1993, 36, 2051– 2058, DOI: 10.1021/jm00067a001[ACS Full Text], [CAS], Google Scholar243https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3sXkslWku7w%253D&md5=99aa7c812225a933a9a311d31d6033a7Excursions in drug discoveryPatchett, Arthur A.Journal of Medicinal Chemistry (1993), 36 (15), 2051-8CODEN: JMCMAR; ISSN:0022-2623.The E. B. Herschberg Award Address of Arthur A. Patchett is given in honor of his contributions in the design of the antihypertensive drugs enalapril and lisinopril and the discovery of the cholesterol-lowering drug lovastatin.
- 244Smith, E. M.; Swiss, G. F.; Neustadt, B. R.; McNamara, P.; Gold, E. H.; Sybertz, E. J.; Baum, T. Angiotensin converting enzyme inhibitors: spirapril and related compounds. J. Med. Chem. 1989, 32, 1600– 1606, DOI: 10.1021/jm00127a033[ACS Full Text], [CAS], Google Scholar244https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1MXlsFCgtb8%253D&md5=6d8ae032a33b98aade4b6b58291524abAngiotensin converting enzyme inhibitors: spirapril and related compoundsSmith, Elizabeth M.; Swiss, Gerald F.; Neustadt, Bernard R.; McNamara, Paul; Gold, Elijah H.; Sybertz, Edmund J.; Baum, ThomasJournal of Medicinal Chemistry (1989), 32 (7), 1600-6CODEN: JMCMAR; ISSN:0022-2623.The synthesis of spirapril (I, R = Et, R1 = Me) (II), spiraprilat (I, R = H, R1 = Me) (III), their (RSS) stereoisomers, and their glycyl (I, R = Et, R1 = H) and lysyl [I, R = H, Et, R1 = (CH2)4NH2] analogs is described. These compds. were evaluated in vivo for inhibition of angiotensin converting enzyme (ACE), and selected compds. were evaluated for in vitro ACE inhibition (II ID50 16 μg/kg; III IC50 0.8 nM, ID50 8 μg/kg). In anesthetized rats (i.v.), esters II and I [R = Et, R1 = (CH2)4NH2] are more potent than enalapril, and diacids III and I [R = H, R1 = (CH2)4NH2] are more potent than enalaprilat in vitro. In the conscious rats (orally), II and enalapril showed potent and sustained activity at doses of 0.03-1 and 0.1-1 mg/kg, resp. From this work, II was selected for clin. evaluation as an antihypertensive agent.
- 245Noble, S.; Sorkin, E. M. A preliminary review of its pharmacology and therapeutic efficacy in the treatment of hypertension. Drugs 1995, 49, 750– 766, DOI: 10.2165/00003495-199549050-00008[Crossref], [PubMed], [CAS], Google Scholar245https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXlvVKku7w%253D&md5=d04b2856affd31cd79ca054aff60f94aSpirapril. A preliminary review of its pharmacology and therapeutic efficacy in the treatment of hypertensionNoble, Stuart; Sorkin, Eugene M.Drugs (1995), 49 (5), 750-66CODEN: DRUGAY; ISSN:0012-6667.A review with 55 refs. Spirapril is a non-sulfhydryl angiotensin-converting enzyme (ACE) inhibitor prodrug which is converted to the active metabolite spiraprilat following oral administration, and which has been evaluated primarily for the treatment of hypertension. In dose-finding studies of patients with mild to severe hypertension, spirapril ≥6mg once daily produced redns. in blood pressure of approx. 10 to 18mm Hg (systolic) and 7 to 13mm Hg (diastolic) [24-h postdose trough readings at the end of the treatment period]. Blood pressure normalization (trough diastolic blood pressure ≤90mm Hg) had occurred in 29 to 50% of patients at the end of these investigations. Spirapril is generally well tolerated and produces an adverse event profile similar to that of other ACE inhibitors. Further comparative trials are needed to fully det. its efficacy with respect to other ACE inhibitors, and a better understanding of its effects on renal function will clarify its role in hypertensive patients with renal failure.
- 246Sybertz, E. J.; Watkins, R. W.; Ahn, H. S.; Baum, T.; La Rocca, P.; Patrick, J.; Leitz, F. Pharmacologic, metabolic, and toxicologic profile of spirapril (SCH 33844), a new angiotensin converting inhibitor. J. Cardiovasc. Pharmacol. 1987, 10, S105– S108, DOI: 10.1097/00005344-198706107-00020[Crossref], [PubMed], [CAS], Google Scholar246https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1cXktlWkurw%253D&md5=c594ce615397b30f16e4c1b230d4d1f7Pharmacologic, metabolic, and toxicologic profile of spirapril (SCH 33844), a new angiotensin converting inhibitorSybertz, Edmund J.; Watkins, Robert W.; Ahn, Ho Sam; Baum, Thomas; La Rocca, Paul; Patrick, James; Leitz, FrederickJournal of Cardiovascular Pharmacology (1987), 10 (Suppl. 7), S105-S108CODEN: JCPCDT; ISSN:0160-2446.Spirapril (SCH 33844) (I) is a new angiotensin-converting enzyme (ACE) inhibitor. SCH 33844 diacid inhibited hydrolysis of hip-his-leu by rabbit lung ACE in a potent (Ki = 0.74 nM), selective, and noncompetitive fashion. SCH 33844 (0.03-1 mg/kg orally) produced dose-related inhibition of angiotensin I (AI) pressor responses in conscious rats with a duration of 24 h at the higher dose. SCH 33844 (0.3-30 mg/kg orally) reduced blood pressure in a dose-related manner in conscious SHR with a 24-h duration. It appears that peripheral vasodilation is the primary mechanism of the antihypertensive action. The metabolic profile of SCH 33844 was evaluated in dogs and rats. The compd. was absorbed in a dose-proportional manner and excreted primary as the diacid form. In contrast to captopril and enalapril, most of the drug (67%) was excreted into the feces following i.v. dosing. Chronic toxicol. evaluation in dogs and rats demonstrated that the drug was relatively devoid of toxicity at oral doses as high as 400 and 450 mg/kg/day, resp. SCH 33844 is a potent, long acting ACE inhibitor with a low level of toxicity and a metabolic fate that differs from that of enalapril and captopril. Its hemodynamic actions suggest that the compd. should be highly effective in the treatment of hypertension and congestive heart failure.
- 247Guitard, C.; Lohmann, F. W.; Alfiero, R.; Ruina, M.; Alvisi, V. Cardiovasc. Drugs Ther. 1997, 11, 449– 457, DOI: 10.1023/A:1007797405850[Crossref], [PubMed], [CAS], Google Scholar247https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXmt12ltL0%253D&md5=bdfda3b6ee0175ff5ef10637c62ebb5fComparison of efficacy of spirapril and enalapril in control of mild-to-moderate hypertensionGuitard, C.; Lohman, F. W.; Alfiero, R.; Ruina, M.; Alvisi, V.Cardiovascular Drugs and Therapy (1997), 11 (3), 449-457CODEN: CDTHET; ISSN:0920-3206. (Kluwer)The efficacy of spirapril, 6 mg once daily, was compared with enalapril, 5-20 mg once daily, in the control of mild-to-moderate hypertension in a placebo-controlled, parallel-group study. A total of 251 patients participated in the study, all of whom underwent a 4-wk washout period on placebo. Thereafter, 100 patients were randomized to spirapril, 6 mg once daily, 101 patients to enalapril, 5-20 mg once daily, and 50 patients remained on placebo. Sitting diastolic blood pressure (DBP) and systolic blood pressure (SBP) were measured at 2-weekly clinic visits. Blood pressure profiles during peak and trough plasma drug concn. (2-4 h and 24-26 h postdose, resp.) were detd. at baseline and 4 and 8 wk after starting the double-blind phase. Compared with placebo, treatment with both spirapril and enalapril resulted in significant redns. (p<0.001) in DBP and SBP. DBP was reduced to a greater extent with spirapril than with enalapril both at peak (17.4 mmHg vs. -14.8 mmHg) and trough (-14.7 mmHg vs. -12.4 mmHg). Thus, although the trough/peak DBP ratios for spirapril and enalapril were very similar (84% vs. 82%), actual redns. in DBP were different. Spirapril and enalapril treatment resulted in similar redns. in SBP at both peak and through levels. Both drugs were well tolerated, and there were very few adverse events of changes in hematol. or biochem. parameters during the study. In conclusion, spirapril, 6 mg once daily, as the initial and maintenance dose, is at least as effective and well tolerated as enalapril individually titrated.
- 248(a) Yamashita, S.; Matsuzawa, Y. Where are we with probucol: a new life for an old drug?. Atherosclerosis 2009, 207, 16– 23, DOI: 10.1016/j.atherosclerosis.2009.04.002[Crossref], [PubMed], [CAS], Google Scholar.248ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtlyrtbbK&md5=6a5ce431e951d9d3947d34afe909a65eWhere are we with probucol: A new life for an old drug?Yamashita, Shizuya; Matsuzawa, YujiAtherosclerosis (Amsterdam, Netherlands) (2009), 207 (1), 16-23CODEN: ATHSBL; ISSN:0021-9150. (Elsevier B.V.)A review. Probucol has a long history of clin. application with established efficacy and safety profiles. Probucol is a potent anti-oxidant drug that was in clin. use during the past few decades for the treatment and prevention of cardiovascular diseases. Here we review the current status of knowledge on the pharmacol., clin. benefits, and the mechanism of actions of this unique drug. Probucol has diverse pharmacol. properties with therapeutic effects on the cardiovascular systems. Its mechanism of pharmacol. actions at the mol. level has recently been elucidated with the new concept of HDL metab. assocd. with cholesteryl ester transfer protein (CETP) or scavenger receptor class B type I (SR-BI). HDL-C redn. may not be a "side effect" but it most likely might reflect a mechanism of action of probucol. Probucol could be reconsidered as an option at least in case statins, which are known to be effective in lowering low-d. lipoproteins (LDL) and coronary artery disease (CAD) risk, are not effective. In particular, a marked CAD risk redn. was recently reported in long-term probucol treatment of patients with heterozygous familial hypercholesterolemia (FH) in Japan. Therefore, probucol could be a more common therapeutic drug for the treatment of patients with FH as well. There is more than enough reason to believe that this old drug has much more to offer than hitherto known.(b) Buckley, M. M.-T.; Goa, K. L.; Price, A. H.; Brogden, R. N. A reappraisal of its pharmacological properties and therapeutic use in hypercholesterolaemia. Drugs 1989, 37, 761– 800, DOI: 10.2165/00003495-198937060-00002[Crossref], [PubMed], [CAS], Google Scholar248bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1MXkvV2lsLo%253D&md5=8f17d5d08d515cd4b8c11af43c996f61Probucol. A reappraisal of its pharmacological properties and therapeutic use in hypercholesterolemiaBuckley, Micaela M. T.; Goa, Karen L.; Price, Allan H.; Brogden, Rex N.Drugs (1989), 37 (6), 761-800CODEN: DRUGAY; ISSN:0012-6667.A review with ∼150 refs. Probucol appears to be of benefit in primary and secondary hyperlipoproteinemia of Types IIa and IIb, and particularly in homozygous familial hypercholesterolemia, with marked effects on xanthomas, and a generally favorable adverse effect profile. There is no evidence to date causally relating occasional QT interval prolongation in patients to any incidence of arrhythmias or sudden death.
- 249(a) Neuworth, M. B.; Laufer, R. J.; Barnhart, J. W.; Sefranka, J. A.; McIntosh, D. D. Synthesis and hypocholesterolemic activity of alkylidenedithio bisphenols. J. Med. Chem. 1970, 13, 722– 725, DOI: 10.1021/jm00298a031[ACS Full Text.], [CAS], Google Scholar249ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE3cXksVGjtrk%253D&md5=5e6a3e7be76f37d20d5b5a47b7220199Synthesis and hypocholesterolemic activity of alkylidenedithio bisphenolsNeuworth, Martin B.; Laufer, Rohert J.; Barnhart, James W.; Sefranka, J. A.; McIntosh, D. D.Journal of Medicinal Chemistry (1970), 13 (4), 722-5CODEN: JMCMAR; ISSN:0022-2623.The synthesis and serum cholesterol lowering properties of a new class of alkylidenedithio bisphenols and related compds. are discussed. Max. activity is shown by 4,4'-(isopropylidenedithio)bis(2,6-di-tertbutylphenol). A few other members of the class show moderate to good activity and these are produced by substitution of a Me group or an iso-Pr group for one tert-Bu group in the phenolic nucleus, or substitution of Et for Me in the isopropylidene moiety. Other reported structural variations resulted in a redn. of activity or, most often, a loss of activity.(b) Carew, T. E.; Schwenke, D. C.; Steinberg, D. Antiatherogenic effect of probucol unrelated to its hypocholesterolemic effect: Evidence that antioxidants in vivo can selectively inhibit low density lipoprotein degradation in macrophage-rich fatty streaks and slow the progression of atherosclerosis in the Watanabe heritable hyperlipidemic rabbit. Proc. Natl. Acad. Sci. U. S. A. 1987, 84, 7725– 7729, DOI: 10.1073/pnas.84.21.7725[Crossref], [PubMed], [CAS], Google Scholar249bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1cXhs1Whtw%253D%253D&md5=331c3283309fd7686ea664350f0ef961Antiatherogenic effect of probucol unrelated to its hypocholesterolemic effect: evidence that antioxidants in vivo can selectively inhibit low density lipoprotein degradation in macrophage-rich fatty streaks and slow the progression of atherosclerosis in the Watanabe heritable hyperlipidemic rabbitCarew, Thomas E.; Schwenke, Dawn C.; Steinberg, DanielProceedings of the National Academy of Sciences of the United States of America (1987), 84 (21), 7725-9CODEN: PNASA6; ISSN:0027-8424.The studies reported here take advantage of the fact that probucol is an effective antioxidant transported in lipoproteins, including LDL (low-d. lipoprotein) and blocks the oxidative modification of LDL in vitro. Results indicated that the rate of degrdn. of LDL in the macrophage-rich fatty-streak lesions of the LDL receptor-deficient rabbit treated with probucol (1% by wt. in the diet) is reduced to ∼50% of that in the lesions of receptor-deficient rabbits not given probucol (but matched for plasma cholesterol levels). In contrast, the rates of degrdn. in the nonlesioned areas of the aorta were no different in probucol-treated and control animals. Most of the LDL degrdn. in fatty-streak lesions takes place in macrophages, whereas in nonlesioned aorta, which contains very few macrophages, the degrdn. is almost exclusively in endothelial cells and smooth muscle cells. Thus, the results are compatible with the postulate that the native LDL taken up and degraded by foam cells in the developing fatty-streak lesions was in part first converted to a form recognized by the scavenger receptor (by oxidative or analogous modification). Finally, and most importantly, treatment with probucol reduced the rate of development of fatty-streak lesions even though plasma cholesterol levels were no lower than lovastatin-treated (control) rabbits.
- 250Meng, C. Q.; Somers, P. K.; Hoong, L. K.; Zheng, X. S.; Ye, Z.; Worsencroft, K. J.; Simpson, J. E.; Hotema, M. R.; Weingarten, M. D.; MacDonald, M. L.; Hill, R. R.; Marino, E. M.; Suen, K.-L.; Luchoomun, J.; Kunsch, C.; Landers, L. K.; Stefanopoulos, D.; Howard, R. B.; Sundell, C. L.; Saxena, U.; Wasserman, M. A.; Sikorski, J. A. Discovery of novel phenolic antioxidants as inhibitors of vascular cell adhesion molecule-1 expression for use in chronic inflammatory diseases. J. Med. Chem. 2004, 47, 6420– 6432, DOI: 10.1021/jm049685u[ACS Full Text], [CAS], Google Scholar250https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXptVyqsrk%253D&md5=2f498806edd0fa66386d676d9710d404Discovery of Novel Phenolic Antioxidants as Inhibitors of Vascular Cell Adhesion Molecule-1 Expression for Use in Chronic Inflammatory DiseasesMeng, Charles Q.; Somers, Patricia K.; Hoong, Lee K.; Zheng, X. Sharon; Ye, Zhihong; Worsencroft, Kimberly J.; Simpson, Jacob E.; Hotema, Martha R.; Weingarten, M. David; MacDonald, Mathew L.; Hill, Russell R.; Marino, Elaine M.; Suen, Ki-Ling; Luchoomun, Jayraz; Kunsch, Charles; Landers, Laura K.; Stefanopoulos, Dimitria; Howard, Randy B.; Sundell, Cynthia L.; Saxena, Uday; Wasserman, Martin A.; Sikorski, James A.Journal of Medicinal Chemistry (2004), 47 (25), 6420-6432CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Vascular cell adhesion mol.-1 (VCAM-1) mediates recruitment of leukocytes to endothelial cells and is implicated in many inflammatory conditions. Since part of the signal transduction pathway that regulates the activation of VCAM-1 expression is redox-sensitive, compds. with antioxidant properties may have inhibitory effects on VCAM-1 expression. Novel phenolic compds. have been designed and synthesized starting from probucol. Many of these compds. demonstrated potent inhibitory effects on cytokine-induced VCAM-1 expression and displayed potent antioxidant effects in vitro. Some of these derivs. inhibited lipopolysaccharide (LPS)-induced secretion of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 from human peripheral blood mononuclear cells (hPBMCs) in a concn.-dependent manner in vitro and showed antiinflammatory effects in an animal model. Two of the compds. are currently in clin. trials for the treatment of rheumatoid arthritis (RA) and prevention of chronic organ transplant rejection, resp.
- 251(a) Meng, C. Q.; Somers, P. K.; Rachita, C. L.; Holt, L. A.; Hoong, L. K.; Zheng, X. S.; Simpson, J. E.; Hill, R. R.; Olliff, L. K.; Kunsch, C. K.; Sundell, C. L.; Parthasarathy, S.; Saxena, U.; Sikorski, J. A.; Wasserman, M. A. Novel phenolic antioxidants as multifunctional inhibitors of inducible VCAM-1 expression for use in atherosclerosis. Bioorg. Med. Chem. Lett. 2002, 12, 2545– 2548, DOI: 10.1016/S0960-894X(02)00516-4[Crossref], [PubMed], [CAS], Google Scholar.251ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XmsVWju7g%253D&md5=1778dcbd0cd9ff0d621c228f8e647fd2Novel phenolic antioxidants as multifunctional inhibitors of inducible VCAM-1 expression for use in atherosclerosisMeng, Charles Q.; Somers, Patricia K.; Rachita, Carolyn L.; Holt, Lisa A.; Hoong, Lee K.; Zheng, X. Sharon; Simpson, Jacob E.; Hill, Russell R.; Olliff, Lynda K.; Kunsch, Charles; Sundell, Cynthia L.; Parthasarathy, Sampath; Saxena, Uday; Sikorski, James A.; Wasserman, Martin A.Bioorganic & Medicinal Chemistry Letters (2002), 12 (18), 2545-2548CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)A series of novel phenolic compds. has been discovered as potent inhibitors of TNF-α-inducible expression of vascular cell adhesion mol.-1 (VCAM-1) with concurrent antioxidant and lipid-modulating properties. Optimization of these multifunctional agents led to the identification of AGI-1067 as a clin. candidate with demonstrated efficacies in animal models of atherosclerosis and hyperlipidemia.(b) Muldrew, K. M.; Franks, A. M. Succinobucol: review of the metabolic, antiplatelet and cardiovascular effects. Expert Opin. Invest. Drugs 2009, 18, 531– 539, DOI: 10.1517/13543780902849244[Crossref], [PubMed], [CAS], Google Scholar251bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXjvVWnsb0%253D&md5=dca022c5167225d3343bf55ca18afbeeSuccinobucol: review of the metabolic, antiplatelet and cardiovascular effectsMuldrew, Kendrea M.; Franks, Amy M.Expert Opinion on Investigational Drugs (2009), 18 (4), 531-539CODEN: EOIDER; ISSN:1354-3784. (Informa Healthcare)A review. Background: Succinobucol (AGI-1067) was developed as a probucol deriv. with anti-inflammatory and antioxidant properties. It has undergone Phase III clin. trials to det. its place in the treatment of atherosclerotic disease. Objective: This paper reviews the available history, pharmacol. and preclin. and clin. trial data of succinobucol. Methods: Data were compiled following review of publications indexed in Medline and International Pharmaceutical Abstrs., industry media releases and relevant bibliogs. Results/conclusion: In preclin. studies, succinobucol exhibited antioxidant, anti-inflammatory, antihyperglycemic and antiplatelet properties; however, these effects have not resulted in a redn. in cardiovascular clin. end points in clin. trials. Although proposed antihyperglycemic effects are being investigated, safety concerns and lack of clear cardiovascular benefit may limit its clin. use as an antihyperglycemic agent.
- 252(a) Groso, G.; Caputo, O.; Ceruti, M.; Biglino, G.; Franzone, J. S.; Cirillo, R. Synthesis and antibronchospastic activity of theophylline thioacetal derivatives. Eur. J. Med. Chem. 1989, 24, 635– 638, DOI: 10.1016/0223-5234(89)90035-4 .(b) Franzone, J. S.; Reboani, M. C.; Biglione, V.; Cirillo, R. Pharmacological and toxicological activities of a new methylxanthine derivative [7-(1,3-dithiolan-2-ylmethyl)-1,3-dimethylxanthine] with antibronchospastic and mucoregulatory properties. Drugs Exp. Clin. Res. 1990, 16, 263– 276[PubMed], [CAS], Google Scholar.252bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXhvF2nsL8%253D&md5=4477119dbd86a0553a4e882411193caePharmacological and toxicological activities of a new methylxanthine derivative [7-(1,3-dithiolan-2-ylmethyl)-1,3-dimethylxanthine] with antibronchospastic and mucoregulatory propertiesFranzone, J. S.; Reboani, M. C.; Biglione, V.; Cirillo, R.Drugs under Experimental and Clinical Research (1990), 16 (6), 263-76CODEN: DECRDP; ISSN:0378-6501.7-(1,3-Dithiolan-2-ylmethyl)-1,3-dimethylxanthine (ABC 99) (I) was studied in animals to evaluate its pharmacol. activity. This compd. had markedly greater antibronchospastic activity in vitro and in vivo than aminophylline. It also had moderate antitussive properties and was an active mucoregulator. ABC 99 acted as an intestinal muscle relaxant, but it had no cardiovascular, urinary, or central-nervous side effects. The action of ABC 99 could be explained by its inhibition of guinea pig lung phosphodiesterases and affinity for adenosine receptors, particularly A2 receptors. ABC 99 had low acute toxicity in animals, indicating that it may be useful for treating asthma and chronic bronchitis.(c) Reboani, M. C.; Franzone, J. S. In vivo anti-inflammatory activity of 7-(1,3-dithiolan-2-ylmethyl)-1,3-dimethylxanthine. Drugs Exp. Clin. Res. 1990, 16, 277– 284[PubMed], [CAS], Google Scholar.252chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXhvF2htbc%253D&md5=e891df751e9a28dd13976c4fe732e801In vivo anti-inflammatory activity of 7-(1,3-dithiolan-2-ylmethyl)-1,3-dimethylxanthineReboani, M. C.; Franzone, J. S.Drugs under Experimental and Clinical Research (1990), 16 (6), 277-84CODEN: DECRDP; ISSN:0378-6501.The title methylxanthine deriv. (ABC 99), which has mucoregulatory and antibronchospastic properties, was studied in rats. ABC 99 had marked anti-inflammatory activity in exptl. trials involving the principal mediators of inflammation (platelet-activating factor [PAF], histamine, serotonin, LTC4-like substances, etc.). It inhibited the formation of edemas induced both by carrageenin and PAF in the rat paw, and reduced the increase in vascular permeability induced by histamine and serotonin. ABC 99 also inhibited PAF-induced pleurisy, reducing the vol. of pleural exudate and the presence of LTC4-like substances in the pleural cavity. When administered subacutely, ABC 99 decreased the formation of granulation tissue caused by the s.c. implantation of cotton pellets in the rat. ABC 99 may be of particular interest in the treatment of respiratory disorders involving obstructive inflammation and bronchial hypersensitivity.(d) Cravanzola, C.; Grosa, G.; Franzone, J. S. Kinetic and metabolic studies of 7-(1,3-dithiolan-2-ylmethyl)-1,3-dimethylxanthine in the rat. Drugs Exp. Clin. Res. 1990, 16, 285– 291[PubMed], [CAS], Google Scholar.252dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXitl2rsLo%253D&md5=d6f672fc5cd4d7b3ae472f72f028b3dbKinetic and metabolic studies of 7-(1,3-dithiolan-2-ylmethyl)-1,3-dimethylxanthine in the ratCravanzola, C.; Grosa, G.; Franzone, J. S.Drugs under Experimental and Clinical Research (1990), 16 (6), 285-91CODEN: DECRDP; ISSN:0378-6501.The kinetics (absorption, tissue distribution and excretion) of the title compd. (ABC 99) (I) were studied in the rat. ABC 99 was administered orally at 10, 30 and 100 mg/kg. ABC 99 was rapidly absorbed, metabolized in the liver, and partially excreted in the urine. It was equally distributed in the tissues, including the brain, although in much lower amts. than those absorbed. Three metabolites were identified: theophylline, which was formed in very small quantities, and 2 isomers (cis and trans) of ABC 99 sulfoxide. The latter 2 compds. formed in greater amts. than theophylline, and the trans-isomer predominated. The metabolites were distributed among the tissues, but did not accumulate. Elimination was virtually complete at 24 h. The pharmacol. activity of ABC 99 (antibronchospastic, mucoregulatory and anti-inflammatory) is probably due to the parent compd., which is absorbed unchanged. However, some activity of the 2 sulfoxides cannot be excluded, as they have a structure analogous to that of ABC 99.(e) Grosa, G.; Caputo, O.; Ceruti, M.; Biglino, G.; Franzone, J. S.; Cravanzola, C. Metabolism of 7-(1,3-dithiolan-2-ylmethyl)-1,3-dimethylxanthine by rat liver microsomes. Diastereoselective metabolism of the 1,3-dithiolane ring. Drug Metab. Dispos. 1991, 19, 454– 457[PubMed], [CAS], Google Scholar.252ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXhvF2jsbw%253D&md5=0b366cc6c209e0011b2343581c74491dMetabolism of 7-(1,3-dithiolan-2-ylmethyl)-1,3-dimethylxanthine by rat liver microsomes. Diastereoselective metabolism of the 1,3-dithiolane ringGrosa, Giorgio; Caputo, Otto; Ceruti, Maurizio; Biglino, Giuseppe; Franzone, Jose Sebastian; Cravanzola, CarloDrug Metabolism and Disposition (1991), 19 (2), 454-7CODEN: DMDSAI; ISSN:0090-9556.The metabolic transformation of the antibronchospastic title compd. (ABC-99) was studied in vitro with a rat liver microsomal prepn. contg. an NAPDH-generating system. About 30% ABC-99 was metabolized and the only metabolic pathway obsd. was oxidn. of the 1,3-dithiolane ring. Two distinct sulfoxides were formed diastereoselectively, the trans isomer being the major product in the ratio 7:3. In contrast to the 1,3-dioxolane ring of doxophylline, the 1,3-dithiolane ring of ABC-99 did not undergo oxidative opening through acetal carbon oxidn. No N-dealkylation to theophylline was obsd. This high regioselectivity in vitro was most likely due to the nucleophilicity of the sulfur atom. The diastereoselective sulfoxidn. was apparently catalyzed by flavin-dependent monooxygenases, as no effect was obsd. with CO treatment, whereas selective thermal inactivation reduced the rate of sulfoxidn.(f) Auret, B. J.; Boyd, D. R.; Dunlop, R.; Drake, A. F. Stereoselectivity during fungal sulphoxidations of 1,3-dithiolanes. J. Chem. Soc., Perkin Trans. 1 1988, 2827– 2829, DOI: 10.1039/p19880002827[Crossref], [CAS], Google Scholar252fhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1cXmt1Knsrw%253D&md5=6136dfd30638e38f89c451ed39b1d236Stereoselectivity during fungal sulfoxidations of 1,3-dithiolanesAuret, Barbara J.; Boyd, Derek R.; Dunlop, Robert; Drake, Alex F.Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999) (1988), (10), 2827-9CODEN: JCPRB4; ISSN:0300-922X.Mono- and disulfoxide products were obtained after addn. of 1,3-dithiolane, 2-methyl-1,3-dithiolane, and 2-t-butyl-1,3-dithiolane as substrates to growing cultures of Aspergillus foetidus, Mortierella isabellina, and a Helminthosporium sp. Enzyme-catalyzed stereodifferentiation between prochiral lone pairs on a S atom gave optically active 1,3-dithiolane 1-oxide (10-65%). The derived optically pure trans-1,3-dithiolane-1,3-dioxide was obtained by fractional recrystn. A stereopreference for the pro-R S atom (61 and 66%) was obsd. during microbial oxidn. of 2-methyl-1,3-dithiolane and 2-t-butyl-1,3-dithiolane, resp. The abs. stereochem. of the dextrorotatory sulfoxide metabolites was assigned the R configuration at the chiral S atoms from CD spectroscopy.
- 253Fulop, F.; Mattinen, J.; Pihlaja, R. Ring-chain tautomerism in 1,2-thiazolidines. Tetrahedron 1990, 46, 6545– 6552, DOI: 10.1016/S0040-4020(01)96019-3[Crossref], [CAS], Google Scholar253https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXmtFemsA%253D%253D&md5=a8aad7f6ce2f771cfb8e6550fd5d5541Ring-chain tautomerism in 1,3-thiazolidinesFulop, Ferenc; Mattinen, Jorma; Pihlaja, KaleviTetrahedron (1990), 46 (18), 6545-52CODEN: TETRAB; ISSN:0040-4020.NMR data show that in general, 1,3-thiazolidines exist as ring tautomers; a detectable amt. of open-chain tautomer was obsd. with (bromohydroxyphenyl)benzothiazoline (eg. I .dblharw. II). The 1,3-thiazolidine ring was ∼104 times more stable that the 1,3-oxazolidine ring.
- 254Singh, G. S. β-lactams in the new millennium. Part-II: Cephems, oxacephems, penams and sulbactam. Mini-Rev. Med. Chem. 2004, 4, 93– 109, DOI: 10.2174/1389557043487547[Crossref], [PubMed], [CAS], Google Scholar254https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhtVagt7o%253D&md5=d250e35611f27756401d720bbcb17fc0β-lactams in the new millennium. Part-II: Cephems, oxacephems, penams and sulbactamSingh, G. S.Mini-Reviews in Medicinal Chemistry (2004), 4 (1), 93-109CODEN: MMCIAE; ISSN:1389-5575. (Bentham Science Publishers Ltd.)A review. β-Lactam ring-contg. compds. such as penicillins, ampicillin, amoxicillin, cephalosporins and carbapenems are among the most famous antibiotics. This article reviews the recent developments in study of cephems, oxacephems, penams and sulbactam. Many of the compds. reviewed have potential antibacterial activity, even against resistant strains such as MRSA, and enzyme inhibitory activity.
- 255Bush, K.; Bradford, P. A. β-Lactams and β-lactamase inhibitors: an overview. Cold Spring Harbor Perspect. Med. 2016, 6, a025247 DOI: 10.1101/cshperspect.a025247[Crossref], [PubMed], [CAS], Google Scholar255https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXns1ygs7o%253D&md5=b66594b35c40b109cdab439c3664aba9β-Lactams and β-lactamase inhibitors: an overviewBush, Karen; Bradford, Patricia A.Cold Spring Harbor Perspectives in Medicine (2016), 6 (8), a025247/1-a025247/23CODEN: CSHPFV; ISSN:2157-1422. (Cold Spring Harbor Laboratory Press)β-Lactams are the most widely used class of antibiotics. Since the discovery of benzylpenicillin in the 1920s, thousands of new penicillin derivs. and related β-lactam classes of cephalosporins, cephamycins, monobactams, and carbapenems have been discovered. Each new class of β-lactam has been developed either to increase the spectrum of activity to include addnl. bacterial species or to address specific resistance mechanisms that have arisen in the targeted bacterial population. Resistance to β-lactams is primarily because of bacterially produced β-lactamase enzymes that hydrolyze the β-lactam ring, thereby inactivating the drug. The newest effort to circumvent resistance is the development of novel broad-spectrum β-lactamase inhibitors that work against many problematic β-lactamases, including cephalosporinases and serine-based carbapenemases, which severely limit therapeutic options. This work provides a comprehensive overview of β-lactam antibiotics that are currently in use, as well as a look ahead to several new compds. that are in the development pipeline.
- 256Szultka, M.; Krzeminski, R.; Jackowski, M.; Buszewski, B. Identification of in vitro metabolites of amoxicillin in human liver microsomes by LC-ESI/MS. Chromatographia 2014, 77, 1027– 1035, DOI: 10.1007/s10337-014-2648-2[Crossref], [PubMed], [CAS], Google Scholar256https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXkslemsbo%253D&md5=e61d287ca77a82a5ca43324bac40e73cIdentification of In Vitro Metabolites of Amoxicillin in Human Liver Microsomes by LC-ESI/MSSzultka, Malgorzata; Krzeminski, Rafal; Jackowski, Marek; Buszewski, BoguslawChromatographia (2014), 77 (15-16), 1027-1035CODEN: CHRGB7; ISSN:0009-5893. (Springer)Amoxicillin (AMOX) metab. in human liver microsomes was studied in vitro using liq. chromatog.-mass spectrometry (LC/MS). Amoxicillin was incubated with human liver microsomes along with NADPH, and the reaction mixt. was analyzed by LC/MS to obtain the specific metabolic profile of the studied antibiotic drug. Pos. electrospray ionization was employed as the ionization source. An ACE C18-column (4.6 mm × 150 mm, 3 μm) was implemented with acetonitrile and water (+0.1 % formic acid) in isocratic mode as the mobile phase at the flow 0.4 mL min-1. The chem. structures of metabolites were proposed on the basis of the accurate mass measurement of the protonated mol. as well as their main product. Six phase I and one phase II metabolites were detected and structurally described. The metab. of AMOX occurred via oxidn., hydroxylation and oxidative deamination, as well as through combination of these reactions. Compd. M7, with glucuronic acid was also obsd. as phase II metabolite. Neither sulfate nor glutathione conjugates were detected. This study presents novel information about the chem. structure of the potential AMOX metabolites and provides vital data for further pharmacokinetic and in vivo metab. studies.
- 257Smith, P. W.; Zuccotto, F.; Bates, R. H.; Martinez-Martinez, M. S.; Read, K. D.; Peet, C.; Epemolu, O. Pharmacokinetics of β-lactam antibiotics: clues from the past to help discover long-acting oral drugs in the future. ACS Infect. Dis. 2018, 4, 1439– 1447, DOI: 10.1021/acsinfecdis.8b00160[ACS Full Text], [CAS], Google Scholar257https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsFOrtbfF&md5=ca8591280316b2c1733e911feb5f0150Pharmacokinetics of β-Lactam Antibiotics: Clues from the Past To Help Discover Long-Acting Oral Drugs in the FutureSmith, Paul W.; Zuccotto, Fabio; Bates, Robert H.; Martinez-Martinez, Maria Santos; Read, Kevin D.; Peet, Caroline; Epemolu, OlaACS Infectious Diseases (2018), 4 (10), 1439-1447CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)A review. β-Lactams represent perhaps the most important class of antibiotics yet discovered. However, despite many years of active research, none of the currently approved drugs in this class combine oral activity with long duration of action. Recent developments suggest that new β-lactam antibiotics with such a profile would have utility in the treatment of tuberculosis. Consequently, the historical β-lactam pharmacokinetic data have been compiled and analyzed to identify possible directions and drug discovery strategies aimed toward new β-lactam antibiotics with this profile.
- 258(a) Drawz, S. M.; Bonomo, R. A. Three decades of β-lactamase inhibitors. Clin. Microbiol. Rev. 2010, 23, 160– 201, DOI: 10.1128/CMR.00037-09[Crossref], [PubMed], [CAS], Google Scholar.258ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXks1Sktbs%253D&md5=27cd9fca0d848185d9c61e5a25d2c601Three decades of β-lactamase inhibitorsDrawz, Sarah M.; Bonomo, Robert A.Clinical Microbiology Reviews (2010), 23 (1), 160-201CODEN: CMIREX; ISSN:0893-8512. (American Society for Microbiology)A review. Since the introduction of penicillin, β-lactam antibiotics have been the antimicrobial agents of choice. Unfortunately, the efficacy of these life-saving antibiotics is significantly threatened by bacterial β-lactamases. β-Lactamases are now responsible for resistance to penicillins, extended-spectrum cephalosporins, monobactams, and carbapenems. In order to overcome β-lactamase-mediated resistance, β-lactamase inhibitors (clavulanate, sulbactam, and tazobactam) were introduced into clin. practice. These inhibitors greatly enhance the efficacy of their partner β-lactams (amoxicillin, ampicillin, piperacillin, and ticarcillin) in the treatment of serious Enterobacteriaceae and penicillin-resistant staphylococcal infections. However, selective pressure from excess antibiotic use accelerated the emergence of resistance to β-lactam-β-lactamase inhibitor combinations. Furthermore, the prevalence of clin. relevant β-lactamases from other classes that are resistant to inhibition is rapidly increasing. There is an urgent need for effective inhibitors that can restore the activity of β-lactams. Here, we review the catalytic mechanisms of each β-lactamase class. We then discuss approaches for circumventing β-lactamase-mediated resistance, including properties and characteristics of mechanism-based inactivators. We next highlight the mechanisms of action and salient clin. and microbiol. features of β-lactamase inhibitors. We also emphasize their therapeutic applications. We close by focusing on novel compds. and the chem. features of these agents that may contribute to a "second generation" of inhibitors. The goal for the next 3 decades will be to design inhibitors that will be effective for more than a single class of β-lactamases.(b) Gonzalez-Bello, C.; Rodríguez, D.; Pernas, M.; Rodríguez, A.; Colchon, E. β-Lactamase inhibitors to restore the efficacy of antibiotics against superbugs. J. Med. Chem. 2020, 63, 1859– 1881, DOI: 10.1021/acs.jmedchem.9b01279[ACS Full Text], [CAS], Google Scholar258bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitVOhsb3J&md5=336d7eb65305b05d909584c6ae3af6a8β-Lactamase Inhibitors To Restore the Efficacy of Antibiotics against SuperbugsGonzalez-Bello, Concepcion; Rodriguez, Diana; Pernas, Marina; Rodriguez, Angela; Colchon, EstherJournal of Medicinal Chemistry (2020), 63 (5), 1859-1881CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. Infections caused by resistant bacteria are nowadays too common and some pathogens have even become resistant to multiple types of antibiotics, in which cases few or even no treatments are available. In recent years, the most successful strategy in anti-infective drug discovery for the treatment of such problematic infections is the combination therapy 'antibiotic + inhibitor of resistance'. These inhibitors allow the repurposing of antibiotics that have already proven to be safe and effective for clin. use. Three main types of compds. have been developed to block the principal bacterial resistance mechanisms: (i) β-lactamase inhibitors; (ii) outer membrane permeabilizers; and (iii) efflux pump inhibitors. This perspective article is focused on β-lactamase inhibitors that disable the most prevalent cause of antibiotic resistance in Gram-neg. bacteria, i.e., the deactivation of the most widely used antibiotics, β-lactams (penicillins, cephalosporines, carbapenems and monobactams), by the prodn. of β-lactamases. An overview of the most recently identified β-lactamase inhibitors and of combination therapy is provided. The article also covers the mechanism of action of the different types of β-lactamase enzymes as a basis for inhibitor design and target inactivation.
- 259English, A. R.; Retsema, J. A.; Girard, A. E.; Lynch, J. E.; Barth, W. E. CP-45,899, a beta-lactamase inhibitor that extends the antibacterial spectrum of beta-lactams: initial bacteriological characterization. Antimicrob. Agents Chemother. 1978, 14, 414– 419, DOI: 10.1128/AAC.14.3.414[Crossref], [PubMed], [CAS], Google Scholar259https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE1MXhtVSm&md5=abcc968e2de6ec25ca4520aebaf9e4c6CP-45,899, a beta-lactamase inhibitor that extends the antibacterial spectrum of beta-lactams: initial bacteriological characterizationEnglish, Arthur R.; Retsema, James A.; Girard, Arthur E.; Lynch, John E.; Barth, Wayne E.Antimicrobial Agents and Chemotherapy (1978), 14 (3), 414-19CODEN: AMACCQ; ISSN:0066-4804.In the presence of low concns. of CP 45,899 (I) [68373-14-8], a β-lactamase [9073-60-3] inhibitor, ampicillin [69-53-4] and other β-lactams readily inhibited the growth of a variety of resistant bacteria that contain β-lactamases. I used alone displayed only weak antibacterial activity, with the notable exception of its potent effects on susceptible and resistant strains of Neisseria gonorrhoeae. I appeared to be somewhat less potent but markedly more stable (in aq. soln.) than the recently described β-lactamase inhibitor clavulanic acid [58001-44-8]. The spectrum extensions provided by the 2 compds. were similar. A 1:1 mixt. of I and ampicillin displayed marked antimicrobial activity in mice exptl. infected with ampicillin-resistant Staphylococcus aureus, Haemophilus influenzae, Klebsiella pneumoniae, and Proteus vulgaris.
- 260English, A. R.; Retsema, J. A.; Girard, A. E.; Lynch, J. E.; Barth, W. E. CP-45,899, a β-lactamase inhibitor that extends the antibacterial spectrum of β-lactams: initial bacteriological characterization. Antimicrob. Agents Chemother. 1978, 14, 414– 419, DOI: 10.1128/AAC.14.3.414[Crossref], [PubMed], [CAS], Google Scholar260https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE1MXhtVSm&md5=abcc968e2de6ec25ca4520aebaf9e4c6CP-45,899, a beta-lactamase inhibitor that extends the antibacterial spectrum of beta-lactams: initial bacteriological characterizationEnglish, Arthur R.; Retsema, James A.; Girard, Arthur E.; Lynch, John E.; Barth, Wayne E.Antimicrobial Agents and Chemotherapy (1978), 14 (3), 414-19CODEN: AMACCQ; ISSN:0066-4804.In the presence of low concns. of CP 45,899 (I) [68373-14-8], a β-lactamase [9073-60-3] inhibitor, ampicillin [69-53-4] and other β-lactams readily inhibited the growth of a variety of resistant bacteria that contain β-lactamases. I used alone displayed only weak antibacterial activity, with the notable exception of its potent effects on susceptible and resistant strains of Neisseria gonorrhoeae. I appeared to be somewhat less potent but markedly more stable (in aq. soln.) than the recently described β-lactamase inhibitor clavulanic acid [58001-44-8]. The spectrum extensions provided by the 2 compds. were similar. A 1:1 mixt. of I and ampicillin displayed marked antimicrobial activity in mice exptl. infected with ampicillin-resistant Staphylococcus aureus, Haemophilus influenzae, Klebsiella pneumoniae, and Proteus vulgaris.
- 261Papp-Wallace, K. M.; Bethel, C. R.; Caillon, J.; Barnes, M. D.; Potel, G.; Bajaksouzian, S.; Rutter, J. D.; Reghal, A.; Shapiro, S.; Taracila, M. A.; Jacobs, M. R.; Bonomo, R. A.; Jacqueline, C. Beyond piperacillin-tazobactam: cefepime and AAI101 as a potent β-lactam-β-lactamase inhibitor combination. Antimicrob. Agents Chemother. 2019, 63, e00105 DOI: 10.1128/AAC.00105-19[Crossref], [PubMed], [CAS], Google Scholar261https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtFeiur%252FE&md5=55a99d1c91a4f138479ad35e507f1c99Beyond piperacillin-tazobactam: cefepime and AAI101 as a potent β-Lactam-β-lactamase inhibitor combinationPapp-Wallace, Krisztina M.; Bethel, Christopher R.; Caillon, Jocelyne; Barnes, Melissa D.; Potel, Gilles; Bajaksouzian, Saralee; Rutter, Joseph D.; Reghal, Amokrane; Shapiro, Stuart; Taracila, Magdalena A.; Jacobs, Michael R.; Bonomo, Robert A.; Jacqueline, CedricAntimicrobial Agents and Chemotherapy (2019), 63 (5), e00105-19/1-e00105-19/17CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)Impeding, as well as reducing, the burden of antimicrobial resistance in Gram-neg. pathogens is an urgent public health endeavor. Our current antibiotic armamentarium is dwindling, while major resistance determinants (e.g., extendedspectrum β-lactamases [ESBLs]) continue to evolve and disseminate around the world. One approach to attack this problem is to develop novel therapies that will protect our current agents. AAI101 is a novel penicillanic acid sulfone β-lactamase inhibitor similar in structure to tazobactam, with one important difference. AAI101 possesses a strategically placed Me group that gives the inhibitor a net neutral charge, enhancing bacterial cell penetration. AAI101 paired with cefepime, also a zwitterion, is in phase III of clin. development for the treatment of serious Gram-neg. infections. Here, AAI101 was found to restore the activity of cefepime against class A ESBLs (e.g., CTX-M-15) and demonstrated increased potency compared to that of piperacillin-tazobactam when tested against an established isogenic panel. The enzymol. properties of AAI101 further revealed that AAI101 possessed a unique mechanism of β-lactamase inhibition compared to that of tazobactam. Addnl., upon reaction with AAI101, CTX-M-15 was modified to an inactive state. Notably, the in vivo efficacy of cefepime-AAI101 was demonstrated using a mouse septicemia model, indicating the ability of AAI101 to bolster significantly the therapeutic efficacy of cefepime in vivo. The combination of AAI101 with cefepime represents a potential carbapenem-sparing treatment regimen for infections suspected to be caused by Enterobacteriaceae expressing ESBLs.
- 262Chen, Y. L.; Chang, C. W.; Hedberg, K. Synthesis of a potent β-lactamase inhibitor-1,1-dioxo-6-(2-pyridyl)methylenepenicillanic acid and its reaction with sodium methoxide. Tetrahedron Lett. 1986, 27, 3449– 3452, DOI: 10.1016/S0040-4039(00)84819-4[Crossref], [CAS], Google Scholar262https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL2sXktVKqtb4%253D&md5=1b214250114c91fad210d2c8d2f61909Synthesis of a potent β-lactamase inhibitor - 1,1-dioxo-6-(2-pyridyl)methylenepenicillanic acid and its reaction with sodium methoxideChen, Yuhpyng L.; Chang, Chi Wu; Hedberg, KirkTetrahedron Letters (1986), 27 (30), 3449-52CODEN: TELEAY; ISSN:0040-4039.1,1-Dioxo-6-(2-pyridyl)methylenepenicillanic acid (I) was preped. in 4 steps from ester II by oxidn., Wittig reaction with 2-picolyltriphenylphosphonium chloride, oxidn. by m-chloroperoxybenzoic acid, and deallylation, and found to be a potent β-lactamase inhibitor. Its reaction with NaOMe was studied to provide insight into its mechanism of enzyme inactivation.
- 263(a) Vazquez-Ucha, J. C.; Maneiro, M.; Martinez-Guitian, M.; Buynak, J.; Bethel, C. R.; Bonomo, R. A.; Bou, G.; Poza, M.; Gonzalez-Bello, C.; Beceiro, A. Activity of the β-lactamase inhibitor LN-1–255 against carbapenem-hydrolyzing class D β-lactamases from Acinetobacter baumannii. Antimicrob. Agents Chemother. 2017, 61, e01172–17 DOI: 10.1128/AAC.01172-17 .(b) Vázquez-Ucha, J. C.; Martínez-Guitián, M.; Maneiro, M.; Conde-Perez, K.; Álvarez-Fraga, L.; Torrens, G.; Oliver, A.; Buynak, J. D.; Bonomo, R. A.; Bou, G.; González-Bello, C.; Poza, M.; Beceiro, A. Therapeutic efficacy of LN-1–255 in combination with imipenem in severe infection caused by carbapenem-resistant Acinetobacter baumannii. Antimicrob. Agents Chemother. 2019, 63, e01092 DOI: 10.1128/AAC.01092-19[Crossref], [PubMed], [CAS], Google Scholar263bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXit1eisbrJ&md5=c53b4095cd6a9de4639d125e2e07b333Therapeutic efficacy of LN-1-255 in combination with imipenem in severe infection caused by carbapenem-resistant Acinetobacter baumanniiVazquez-Ucha, Juan Carlos; Martinez-Guitian, Marta; Maneiro, Maria; Conde-Perez, Kelly; Alvarez-raga, Laura; Torrens, Gabriel; Oliver, Antonio; Buynak, John D.; Bonomo, Robert A.; Bou, German; Gonzalez-Bello, Concepcion; Poza, Margarita; Beceiroa, AlejandroAntimicrobial Agents and Chemotherapy (2019), 63 (10), e01092-19CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)The carbapenem-hydrolyzing class D β-lactamases (CHDLs) are the main mechanism of carbapenem resistance in Acinetobacter baumannii. CHDLs are not effectively inactivated by clin. available β-lactam-type inhibitors. We have previously described the in vitro efficacy of the inhibitor LN-1-255 in combination with carbapenems. The aim of this study was to compare the efficacy of LN-1-255 with that of imipenem in murine pneumonia using A. baumannii strains carrying their most extended carbapenemases, OXA-23 and OXA-24/40. The blaOXA-23 and blaOXA-24/40 genes were cloned into the carbapenem-susceptible A. baumannii ATCC 17978 strain. Clin. isolates Ab1 and JC12/04, producing the enzymes OXA-23 and OXA-24/40, resp., were used in the study. Pharmacokinetic (PK) parameters were detd. An exptl. pneumonia model was used to evaluate the efficacy of the combined imipenem-LN-1-255 therapy. MICs of imipenem decreased between 32- and 128-fold in the presence of LN-1-255. I.m. treatment with imipenem-LN-1-255 (30/50 mg/kg) decreased the bacterial burden by (i) 4 and 1.7 log10 CFU/g lung in the infection with the ATCC 17978-OXA-23 and Ab1 strains, resp., and by (ii) 2.5 and 4.5 log10 CFU/g lung in the infection produced by the ATCC 17978-OXA-24/40 and the JC12/04 strains, resp. In all assays, combined therapy offered higher protection against pneumonia than that provided by monotherapy. No toxicity was obsd. in treated mice. Imipenem treatment combined with LN-1-255 treatment significantly reduced the severity of infection by carbapenem-resistant A. baumannii strains carrying CHDLs. Preclin. assays demonstrated the potential of LN-1-255 and imipenem therapy as a new antibacterial treatment.
- 264Lee, M.-H. H.; Graham, G. G.; Williams, K. M.; Day, R. O. A benefit-risk assessment of benzbromarone in the treatment of gout: was its withdrawal from the market in the best interest of patients?. Drug Saf. 2008, 31, 643– 665, DOI: 10.2165/00002018-200831080-00002[Crossref], [PubMed], [CAS], Google Scholar264https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXht1CmtbzO&md5=2f06e6058b5d2b0dddaad2285bae5053A benefit-risk assessment of benzbromarone in the treatment of gout: was its withdrawal from the market in the best interest of patients?Lee, Ming-Han H.; Graham, Garry G.; Williams, Kenneth M.; Day, Richard O.Drug Safety (2008), 31 (8), 643-665CODEN: DRSAEA; ISSN:0114-5916. (Wolters Kluwer Health)A review. Benzbromarone, a potent uricosuric drug, was introduced in the 1970s and was viewed as having few assocd. serious adverse reactions. It was registered in about 20 countries throughout Asia, South America and Europe. In 2003, the drug was withdrawn by Sanofi-Synthelabo, after reports of serious hepatotoxicity, although it is still marketed in several countries by other drug companies. The withdrawal has greatly limited its availability around the world, and increased difficulty in accessing it in other countries where it has never been available. The overall aim of this paper is to det. if the withdrawal of benzbromarone was in the best interests of gouty patients and to present a benefit-risk assessment of benzbromarone. To det. this, we examd. (i) the clin. benefits assocd. with benzbromarone treatment and compared them with the success of alternative therapies such as allopurinol and probenecid, particularly in patients with renal impairment; (ii) the attribution of the reported cases of hepatotoxicity to treatment with benzbromarone; (iii) the incidence of hepatotoxicity possibly due to benzbromarone; (iv) adverse reactions to allopurinol and probenecid. From these analyses, we present recommendations on the use of benzbromarone. Large redns. in plasma urate concns. in patients with hyperuricemia are achieved with benzbromarone and most patients normalize their plasma urate. The half-life of benzbromarone is generally short (about 3 h); however, a uricosuric metabolite, 6-hydroxybenzbromarone, has a much longer half-life (up to 30 h) and is the major species responsible for the uricosuric activity of benzbromarone, although its metab. by cytochrome P 450 (CYP) 2C9 in the liver may vary between patients as a result of polymorphisms in this enzyme. It is effective in patients with moderate renal impairment. Std. dosages of benzbromarone (100 mg/day) tend to produce greater hypouricemic effects than std. doses of allopourinol (300 mg/day) or probenecid (1000 mg/day). Adverse effects assocd. with benzbromarone are relatively infrequent, but potentially severe. Four cases of benzbromarone-induced hepatotoxicity were identified from the literature. Eleven cases have been reported by Sanofi-Synthelabo, but details are not available in the public domain. Only one of the four published cases demonstrated a clear relationship between the drug and liver injury as demonstrated by rechallenge. The other three cases lacked incontrovertible evidence to support a diagnosis of benzbromarone-induced hepatotoxicity. If all the reported cases are assumed to be due to benzbromarone, the estd. risk of hepatotoxicity in Europe was approx. 1 in 17 000 patients but may be higher in Japan. Benzbromarone is also an inhibitor of CYP2C9 and so may be involved in drug interactions with drugs dependent on this enzyme for clearance, such as warfarin. Alternative drugs to benzbromarone have significant adverse reactions. Allopurinol is assocd. with rare life-threatening hypersensitivity syndromes; the risk of these reactions is approx. 1 in 56 000. Rash occurs in approx. 2% of patients taking allopurinol and usually leads to cessation of prescription of the drug. Probenecid has also been assocd. with life-threatening reactions in a very small no. of case reports, but it frequently interacts with many renally excreted drugs. Febuxostat is a new xanthine oxidoreductase inhibitor, which is still in clin. trials, but abnormal liver function is the most commonly reported adverse reaction. Even assuming a causal relationship between benzbromarone and hepatotoxicity in the identified cases, benefit-risk assessment based on total exposure to the drug does not support the decision by the drug company to withdraw benzbromarone from the market given the paucity of alternative options. It is likely that the risks of hepatotoxicity could be ameliorated by employing a graded dosage increase, together with regular monitoring of liver function. Detn. of CYP2C9 status and consideration of potential interactions through inhibition of this enzyme should be considered. The case for wider and easier availability of benzbromarone for treating selected cases of gout is compelling, particularly for patients in whom allopurinol produces insufficient response or toxicity. We conclude that the withdrawal of benzbromarone was not in the best interest of patients with gout.
- 265(a) Uda, J.; Kobashi, S.; Miyata, S.; Ashizawa, N.; Matsumoto, K.; Iwanaga, T. Discovery of dotinurad (FYU-981), a new phenol derivative with highly potent uric acid lowering activity. ACS Med. Chem. Lett. 2020, 11, 2017– 2023, DOI: 10.1021/acsmedchemlett.0c00176[ACS Full Text.], [CAS], Google Scholar265ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtl2rsrzI&md5=d9b7f1b3d44de3d66b2dfff439360b4cDiscovery of Dotinurad (FYU-981), a New Phenol Derivative with Highly Potent Uric Acid Lowering ActivityUda, Junichiro; Kobashi, Seiichi; Miyata, Sachiho; Ashizawa, Naoki; Matsumoto, Koji; Iwanaga, TakashiACS Medicinal Chemistry Letters (2020), 11 (10), 2017-2023CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)To derive new uricosuric agents, novel phenol derivs. were synthesized to overcome the disadvantages of benzbromarone (BBR), attributed by its structural features. Herein, we report the discovery of new phenol derivs. with a 1,1-dioxo-1,2-dihydro-3H-1,3-benzothiazole scaffold. The selected compd. 11 (dotinurad, 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-1,2-dihydro-3H-1,3-benzothiazole, FYU-981, [1285572-51-1]) demonstrated remarkable inhibitory activity on uric acid uptake by primary human renal proximal tubule epithelial cells (RPTECs) and URAT1-mediated uric acid transport, with weak inhibitory activity against mitochondrial respiration. Dotinurad also displayed favorable pharmacokinetic profiles and higher potency in decreasing uric acid than BBR did in Cebus monkeys. Dotinurad has been approved as a new uricosuric medicine in Japan. Our strategy, which focuses on the structural features resulting in unfavorable effects, could be applied to the future developments of other drugs with disadvantages, particularly those having a bis-aryl ketone structure.(b) Omura, K.; Miyata, K.; Kobashi, S.; Ito, A.; Fushimi, M.; Uda, J.; Sasaki, T.; Iwanaga, T.; Ohashi, T. Ideal pharmacokinetic profile of dotinurad as a selective reabsorption inhibitor. Drug Metab. Pharmacokinet. 2020, 35, 313– 320, DOI: 10.1016/j.dmpk.2020.03.002[Crossref], [PubMed], [CAS], Google Scholar265bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXkvFagsb4%253D&md5=e2c708f51a52f2c2c49259f5c5e58e01Ideal pharmacokinetic profile of dotinurad as a selective urate reabsorption inhibitorOmura, Koichi; Miyata, Kengo; Kobashi, Seiichi; Ito, Azusa; Fushimi, Masahiko; Uda, Junichiro; Sasaki, Tomomitsu; Iwanaga, Takashi; Ohashi, TetsuoDrug Metabolism and Pharmacokinetics (2020), 35 (3), 313-320CODEN: DMPRB8; ISSN:1347-4367. (Elsevier B.V.)Dotinurad, a novel selective urate reabsorption inhibitor (SURI), has potent inhibitory effects at low doses on the uptake of urate by urate transporter 1 (URAT1, solute carrier family 22 member 12 [SLC22A12]), localized at the apical membrane of renal proximal tubular cells. This study sought to clarify the pharmacokinetic (PK) profile of dotinurad. In rats, monkeys, and humans, the apparent distribution vol. (0.257, 0.205, and 0.182 L/kg, resp.) and oral clearance (0.054, 0.037, and 0.013 L·h-1·kg-1, resp.) of dotinurad were very low, whereas plasma and luminal concns. were adequately maintained at high levels. In addn., species differences were scarcely obsd. with plasma protein binding of 99.4%. The main metabolite was dotinurad glucuronide (no specific metabolites in humans), and percentage excretion of unchanged dotinurad was low in all the investigated species. The risk of drug interaction with dotinurad was expected to be low, because it weakly inhibits metabolic enzymes such as cytochrome P 450 (CYP). In conclusion, low-dose dotinurad exhibited excellent pharmacol. effects as well as ideal PK properties as a SURI.
- 266Hansen, A. H.; Sergeev, E.; Bolognini, D.; Sprenger, R. R.; Ekberg, J. H.; Ejsing, C. S.; McKenzie, C. J.; Ulven, E. R.; Milligan, G.; Ulven, T. Discovery of a potent thiazolidine free fatty acid receptor 2 agonist with favorable pharmacokinetic properties. J. Med. Chem. 2018, 61, 9534– 9550, DOI: 10.1021/acs.jmedchem.8b00855[ACS Full Text], [CAS], Google Scholar266https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhslKqtrbO&md5=932b2b9e1a00988ee067bb34b2d871acDiscovery of a Potent Thiazolidine Free Fatty Acid Receptor 2 Agonist with Favorable Pharmacokinetic PropertiesHansen, Anders Hoejgaard; Sergeev, Eugenia; Bolognini, Daniele; Sprenger, Richard R.; Ekberg, Jeppe Hvidtfeldt; Ejsing, Christer S.; McKenzie, Christine J.; Rexen Ulven, Elisabeth; Milligan, Graeme; Ulven, TrondJournal of Medicinal Chemistry (2018), 61 (21), 9534-9550CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Free fatty acid receptor 2 (FFA2/GPR43) is a receptor for short-chain fatty acids reported to be involved in regulation of metab., appetite, fat accumulation, and inflammatory responses and is a potential target for treatment of various inflammatory and metabolic diseases. By bioisosteric replacement of the central pyrrolidine core of a previously disclosed FFA2 agonist with a synthetically more tractable thiazolidine, authors were able to rapidly synthesize and screen analogs modified at both the 2- and 3-positions on the thiazolidine core. Herein, they report SAR exploration of thiazolidine FFA2 agonists and the identification of (2R,4R)-2-(2-chlorophenyl)-3-(4-(3,5-dimethylisoxazol-4-yl)benzoyl)thiazolidine-4-carboxylic acid (31, TUG-1375), a compd. with significantly increased potency (7-fold in a cAMP assay) and reduced lipophilicity (50-fold reduced clogP) relative to the pyrrolidine lead structure. The compd. has high soly., high chem., microsomal, and hepatocyte stability, and favorable pharmacokinetic properties and was confirmed to induce human neutrophil mobilization and to inhibit lipolysis in murine adipocytes.
- 267(a) Edmondson, S. D.; Mastracchio, A.; Beconi, M.; Colwell, L. F.; Habulihaz, B.; He, H.; Kumar, S.; Leiting, B.; Lyons, K. A.; Mao, A.; Marsilio, F.; Patel, R. A.; Wu, J. K.; Zhu, L.; Thornberry, N.; Weber, A.; Parmee, E. R. Potent and selective proline derived dipeptidyl peptidase IV inhibitors. Bioorg. Med. Chem. Lett. 2004, 14, 5151– 5155, DOI: 10.1016/j.bmcl.2004.07.056[Crossref], [PubMed], [CAS], Google Scholar.267ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXns1Ohu7o%253D&md5=a60ab88a8e75d41cb7eee30b4c950005Potent and selective proline derived dipeptidyl peptidase IV inhibitorsEdmondson, Scott D.; Mastracchio, Anthony; Beconi, Maria; Colwell, Lawrence F.; Habulihaz, Bahanu; He, Huaibing; Kumar, Sanjeev; Leiting, Barbara; Lyons, Kathryn A.; Mao, Ann; Marsilio, Frank; Patel, Reshma A.; Wu, Joseph K.; Zhu, Lan; Thornberry, Nancy A.; Weber, Ann E.; Parmee, Emma R.Bioorganic & Medicinal Chemistry Letters (2004), 14 (20), 5151-5155CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Inhouse screening of the Merck sample collection identified proline derived homophenylalanine I as a DPP-IV inhibitor with modest potency (DPP-IV IC50 = 1.9 μM). Optimization of I led to a compd. which is among the most potent and selective DPP-IV inhibitors discovered to date.(b) Park, W. S.; Kang, S. K.; Jun, M. A.; Shin, M. S.; Kim, K. Y.; Rhee, S. D.; Bae, M. A.; Kim, M. S.; Kim, K. R.; Kang, N. S.; Yoo, S.; Lee, J. O.; Song, D. Y.; Silinski, P.; Schneider, S. E.; Ahn, J. H.; Kim, S. S. Discovery of β-aminoacyl containing thiazolidine derivatives as potent and selective dipeptidyl peptidase IV inhibitors. Bioorg. Med. Chem. Lett. 2011, 21, 1366– 1370, DOI: 10.1016/j.bmcl.2011.01.041[Crossref], [PubMed], [CAS], Google Scholar267bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXit1GmtLk%253D&md5=df0884cce72f1340b9610310682c2735Discovery of β-aminoacyl containing thiazolidine derivatives as potent and selective dipeptidyl peptidase IV inhibitorsPark, Woul Seong; Kang, Seung Kyu; Jun, Mi Ae; Shin, Mi Sik; Kim, Ki Young; Rhee, Sang Dal; Bae, Myung Ae; Kim, Min Sun; Kim, Kwang Rok; Kang, Nam Sook; Yoo, Sung-eun; Lee, Jie Oh; Song, Dong Hyun; Silinski, Peter; Schneider, Stephen Edward; Ahn, Jin Hee; Kim, Sung SooBioorganic & Medicinal Chemistry Letters (2011), 21 (5), 1366-1370CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A series of β-aminoacyl contg. thiazolidine derivs. was synthesized and evaluated for their ability to inhibit DPP-IV. Several thiazolidine derivs. with an acid moiety were found to be potent DPP-IV inhibitors. Among them, I is the most active in this series with an IC50 value of 1 nM, and it showed excellent selectivity over DPP-IV related enzymes including DPP-2, DPP-8, and DPP-9. I is chem. and metabolically stable, and showed no CYP inhibition, hERG binding or cytotoxicity. The Et ester prodrug of I showed good in vivo DPP-IV inhibition after oral administration in rat and dog models.
- 268Carzaniga, L.; Amari, G.; Rizzi, A.; Capaldi, C.; Fanti, R. D.; Ghidini, E.; Villetti, G.; Carnini, C.; Moretto, N.; Facchinetti, F.; Caruso, P.; Marchini, G.; Battipaglia, L.; Patacchini, R.; Cenacchi, V.; Volta, R.; Amadei, F.; Pappani, A.; Capacchi, S.; Bagnacani, V.; Delcanale, M.; Puccini, P.; Catinella, S.; Civelli, M.; Armani, E. Discovery and optimization of thiazolidinyl and pyrrolidinyl derivatives as Inhaled PDE4 inhibitors for respiratory diseases. J. Med. Chem. 2017, 60, 10026– 10046, DOI: 10.1021/acs.jmedchem.7b01044[ACS Full Text], [CAS], Google Scholar268https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvFWhs7rI&md5=44f2dc4fbac0d34580ff06d6cbca352dDiscovery and Optimization of Thiazolidinyl and Pyrrolidinyl Derivatives as Inhaled PDE4 Inhibitors for Respiratory DiseasesCarzaniga, Laura; Amari, Gabriele; Rizzi, Andrea; Capaldi, Carmelida; De Fanti, Renato; Ghidini, Eleonora; Villetti, Gino; Carnini, Chiara; Moretto, Nadia; Facchinetti, Fabrizio; Caruso, Paola; Marchini, Gessica; Battipaglia, Loredana; Patacchini, Riccardo; Cenacchi, Valentina; Volta, Roberta; Amadei, Francesco; Pappani, Alice; Capacchi, Silvia; Bagnacani, Valentina; Delcanale, Maurizio; Puccini, Paola; Catinella, Silvia; Civelli, Maurizio; Armani, ElisabettaJournal of Medicinal Chemistry (2017), 60 (24), 10026-10046CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Phosphodiesterase 4 (PDE4) is a key cAMP-metabolizing enzyme involved in the pathogenesis of inflammatory disease, and its pharmacol. inhibition has been shown to exert therapeutic efficacy in chronic obstructive pulmonary disease (COPD). Herein, the authors describe a drug discovery program aiming at the identification of novel classes of potent PDE4 inhibitors suitable for pulmonary administration. Starting from a previous series of benzoic acid esters, the authors explored the chem. space in the solvent-exposed region of the enzyme catalytic binding pocket. Extensive structural modifications led to the discovery of a no. of heterocycloalkyl esters as potent in vitro PDE4 inhibitors. (S*,S**)-18e (3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((S)-1-((3-(dimethylcarbamoyl)phenyl)sulfonyl)pyrrolidine-2-carbonyl)oxy)ethyl)pyridine 1-oxide) and (S*,S**)-22e (3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((S)-3-(3-(dimethylcarbamoyl)phenylsulfonyl)thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide), in particular, exhibited optimal in vitro ADME and pharmacokinetics properties and dose-dependently counteracted acute lung eosinophilia in an exptl. animal model. The optimal biol. profile as well as the excellent solid-state properties suggest that both compds. have the potential to be effective topical agents for treating respiratory inflammatory diseases.
- 269Chen, T.; Reich, N. W.; Bell, N.; Finn, P. D.; Rodriguez, D.; Kohler, J.; Kozuka, K.; He, L.; Spencer, A. G.; Charmot, D.; Navre, M.; Carreras, C. W.; Koo-McCoy, S.; Tabora, J.; Caldwell, J. S.; Jacobs, J. W.; Lewis, J. G. Design of gut-restricted thiazolidine agonists of G protein-coupled bile acid receptor 1 (GPBAR1, TGR5). J. Med. Chem. 2018, 61, 7589– 7613, DOI: 10.1021/acs.jmedchem.8b00308[ACS Full Text], [CAS], Google Scholar269https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsFOksbjF&md5=d379f4ce804cfe94bb8543a88429a92fDesign of Gut-Restricted Thiazolidine Agonists of G Protein-Coupled Bile Acid Receptor 1 (GPBAR1, TGR5)Chen, Tao; Reich, Nicholas William; Bell, Noah; Finn, Patricia D.; Rodriguez, David; Kohler, Jill; Kozuka, Kenji; He, Limin; Spencer, Andrew G.; Charmot, Dominique; Navre, Marc; Carreras, Christopher W.; Koo-McCoy, Samantha; Tabora, Jocelyn; Caldwell, Jeremy S.; Jacobs, Jeffrey W.; Lewis, Jason GustafJournal of Medicinal Chemistry (2018), 61 (17), 7589-7613CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Bile acid signaling and metab. in the gastrointestinal tract have wide-ranging influences on systemic disease. G protein-coupled bile acid receptor 1 (GPBAR1, TGR5) is one of the major effectors in bile acid sensing, with demonstrated influence on metabolic, inflammatory and proliferative processes. The pharmacol. utility of TGR5 agonists has been limited by systemic target-related effects such as excessive gallbladder filling and blockade of gallbladder emptying. Gut-restricted TGR5 agonists, however, have the potential to avoid these side effects and consequently be developed into drugs with acceptable safety profiles. The authors describe the discovery and optimization of a series of gut-restricted TGR5 agonists that elicit a potent response in mice, with minimal gallbladder-related effects. The series includes 12 (4-(2,5-Dichloro-4-{[(4R)-4-[(4-cyclopropyl-1,2,3,4-tetrahydroquinoxalin-1-yl)carbonyl]-1,3-thiazolidin-3-yl]methyl}-phenoxymethyl)-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]-benzamide) (TGR5 EC50: human, 143 nM; mouse, 1.2 nM), a compd. with minimal systemic availability that may have therapeutic value to patients with type 2 diabetes mellitus, non-alc. steatohepatitis or inflammatory bowel disease.
- 270Tobias, P. S.; Kallen, R. G. Kinetics and equilibriums of the reaction of pyridoxal 5′-phosphate with ethylenediamine to form Schiff bases and cyclic geminal diamines. Evidence for kinetically competent geminal diamine intermediates in transimination sequences. J. Am. Chem. Soc. 1975, 97, 6530– 6539, DOI: 10.1021/ja00855a041[ACS Full Text], [CAS], Google Scholar270https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE2MXmtVGntbs%253D&md5=2b9636fc572d3dcd47785dd41ed119e2Kinetics and equilibriums of the reaction of pyridoxal 5'-phosphate with ethylenediamine to form Schiff bases and cyclic geminal diamines. Evidence for kinetically competent geminal diamine intermediates in transimination sequencesTobias, Peter S.; Kallen, Roland G.Journal of the American Chemical Society (1975), 97 (22), 6530-9CODEN: JACSAT; ISSN:0002-7863.Ethylenediamine and pyridoxal 5'-phosphate form Schiff bases and cyclic geminal diamines (imidazolidines) in aq. soln. in the pH range 7.5 to 14. The various pH-independent open chain cyclic tautomerization consts. and the microscopic proton dissociation consts. for the Schiff bases and cyclic geminal diamines were detd. from (1) the pH dependencies of electronic absorption spectra, (2) from the pH dependency of apparent assocn. consts. for addn. of ethylenediamine to pyridoxal 5'-phosphate and (3) model compds. The rates of the interconversion of the open chain Schiff bases and cyclic geminal diamines obtained from temp.-jump relaxation expts. appear to be hydronium ion catalyzed in the pH range 11.5 to 13 with kinetic consts. reaching values ∼105 sec-1 at the lower pH limit. This rate const. for a reaction which is in effect an intramol. transimination sequence is about 107 larger than the rate consts. for the alternative transimination route involving Schiff base hydrolysis and reformation and suggests that the transimination reactions in which the pyridoxal 5'-phosphate moiety is transferred from the ε-amino group of a lysine residue of an enzyme to be the α-amino group of a substrate amino acid at the active sites of pyridoxal 5'-phosphate dependent enzymes almost certainly involve enzyme bound geminal diamine intermediates and not enzyme bound pyridoxal 5'-phosphate itself. From a comparison of the rates of the intramol. transimination process and the turnover numbers of pyridoxal 5'-phosphate dependent enzymes, it appears that such enzymes may not need to catalyze the transimination process by contributions that are other than entropic in nature.
- 271Faine, S.; Harper, M. Independent antibiotic actions of hetacillin and ampicillin revealed by fast methods. Antimicrob. Agents Chemother. 1973, 3, 15– 18, DOI: 10.1128/AAC.3.1.15[Crossref], [PubMed], [CAS], Google Scholar271https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE3sXhtlaht7k%253D&md5=41ab8d1c32bbf0f22b0f21390af1b7b8Independent antibiotic actions of hetacillin and ampicillin revealed by fast methodsFaine, S.; Harper, M.Antimicrobial Agents and Chemotherapy (1973), 3 (1), 15-18CODEN: AMACCQ; ISSN:0066-4804.In methods developed for the fast measurement of Escherichia coli or Staphylococcus aureus growth inhibition by hetacillin (I) [3511-16-8] or its hydrolysis product ampicillin [69-53-4], the rate of inhibition was a function of antibiotic concn. I had a half-life of 20 min at 37.deg. and pH 6.7, and was much less susceptible to penicillinase than was ampicillin. Thus, the use of high concns. of antibiotic in the presence of penicillinase permitted the demonstration of an independent antibiotic action of I.
- 272(a) Balkovec, J. M.; Hughes, D. L.; Masurekar, P. S.; Sable, C. A.; Schwartz, R. E.; Singh, S. B. Discovery and development of first in class antifungal caspofungin (CANCIDAS®) - a case study. Nat. Prod. Rep. 2014, 31, 15– 34, DOI: 10.1039/C3NP70070D[Crossref], [PubMed], [CAS], Google Scholar.272ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvVyqsr7E&md5=8064e3108df090056d00d50906c451afDiscovery and development of first in class antifungal caspofungin (CANCIDAS)-A case studyBalkovec, James M.; Hughes, David L.; Masurekar, Prakash S.; Sable, Carole A.; Schwartz, Robert E.; Singh, Sheo B.Natural Product Reports (2014), 31 (1), 15-34CODEN: NPRRDF; ISSN:0265-0568. (Royal Society of Chemistry)A review. This paper describes a fifteen year journey from concept to clin. discovery and development of the first in class caspofungin acetate (CANCIDAS) a parenteral antifungal agent. Caspofungin is a semisynthetic deriv. of pneumocandin B0, a naturally occurring, lipophilic cyclic peptide isolated from the fungus, Glarea lozoyensis. While the echinocandins had been previously studied for antifungal activity by several organizations, the class was dropped for a variety of reasons. Merck subsequently initiated a research program leading to the discovery and development of caspofungin. The multitude of challenges that ensued during the discovery and development process and which were successfully resolved by multi-disciplinary teams constitute the content of this article. The article consists of five sections that describe the discovery and development of caspofungin in chronol. order: (i) discovery of the natural product pneumocandin B0 from fungal fermns., (ii) fermn. development to improve the titer of pneumocandin B0 to make it com. viable, (iii) semisynthetic modification by medicinal chem. to successfully improve the properties of pneumocandin B0 leading to the discovery of caspofungin, (iv) development of com. semisynthesis and purifn. and formulation development to improve stability and (v) clin. development and approval of CANCIDAS as an antifungal drug which subsequently saved thousands of lives.(b) Bouffard, F. A.; Hammond, M. L.; Arison, B. H. Pneumocandin Bo acid degradate. Tetrahedron Lett. 1995, 36, 1405– 1408, DOI: 10.1016/0040-4039(95)00017-7[Crossref], [CAS], Google Scholar272bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXktF2ntro%253D&md5=6ea85d7cabb42e519e44ce6ca0282472Pneumocandin B0 acid degrateBouffard, F. Aileen; Hammond, Milton L.; Arison, Byron H.Tetrahedron Letters (1995), 36 (9), 1405-8CODEN: TELEAY; ISSN:0040-4039. (Elsevier)Acid-catalyzed ionization of pneumocandin B0 in a polar aprotic solvent produces the internally cyclized dehydration product I (R = 10, 12-dimethylmyristoyl).
- 273Kurtz, M. B.; Douglas, C.; Marrinan, J.; Nollstadt, K.; Onishi, J.; Dreikorn, S.; Milligan, J.; Mandala, S.; Thompson, J.; Balkovec, J. M. Increased antifungal activity of L-733,560, a water-soluble, semisynthetic pneumocandin, is due to enhanced inhibition of cell wall synthesis. Antimicrob. Agents Chemother. 1994, 38, 2750– 2757, DOI: 10.1128/AAC.38.12.2750[Crossref], [PubMed], [CAS], Google Scholar273https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXisVCrsLg%253D&md5=78d72afc2fd06295660f1ec1e60d094eIncreased antifungal activity of L-733,560, a water-soluble, semisynthetic pneumocandin, is due to enhanced inhibition of cell wall synthesisKurtz, M. B.; Douglas, C.; Marrinan, J.; Nollstadt, K.; Onishi, J.; Dreikorn, S.; Milligan, J.; Mandala, S.; Thompson, J.; et al.Antimicrobial Agents and Chemotherapy (1994), 38 (12), 2750-7CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)The pneumocandins are natural lipopeptide products of the echinocandin class which inhibit the synthesis of 1,3-β-D-glucan in susceptible fungi. The lack of a corresponding pathway in mammalian hosts makes this mode of action an attractive one for treating systemic infections. Substitution by an aminoethyl ether at the hemiaminal and dehydration and redn. of the glutamine of pneumocandin Bo produced a semisynthetic compd. (L-733,560) with intrinsic water soly., significantly increased potency, and a broader antifungal spectrum. To evaluate the mechanism for the improved antifungal efficacy, we detd. that L-733,560 was a more potent inhibitor of glucan synthase activity in vitro, did not affect the other membrane-bound enzymes tested, conferred susceptibility to lysis in the absence of osmotic support, and did not disrupt currents in liposomal bilayers or 86Rb+ fluxes from liposomes. In Aspergillus species L-733,560 also produced the same morphol. alterations as pneumocandin Bo. A stereoisomer of L-733,560 with poor antifungal activity was a weak inhibitor of glucan synthase. All of these results support the notion that the enhanced antifungal activity of L-733,560 is achieved by superior inhibition of glucan synthesis and not by nonspecific membrane effects or a second mode of action.
- 274(a) Bartizal, K.; Gill, C. J.; Abruzzo, G. K.; Flattery, A. M.; Kong, L.; Scott, P. M.; Smith, J. G.; Leighton, C. E.; Bouffard, A.; Dropinski, J. F.; Balkovec, J. In vitro preclinical evaluation studies with the echinocandin antifungal MK-0991 (L-743,872). Antimicrob. Agents Chemother. 1997, 41, 2326– 2332, DOI: 10.1128/AAC.41.11.2326[Crossref], [PubMed], [CAS], Google Scholar.274ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXntFKgu70%253D&md5=3f1763f897bef85dd48a6ef77ca18b37In vitro preclinical evaluation studies with the echinocandin antifungal MK-0991 (L-743,872)Bartizal, Ken; Gill, Charles J.; Abruzzo, George K.; Flattery, Amy M.; Kong, Li; Scott, Patricia M.; Smith, Jeffrey G.; Leighton, Claire E.; Bouffard, Aileen; Dropinski, James F.; Balkovec, JamesAntimicrobial Agents and Chemotherapy (1997), 41 (11), 2326-2332CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)The echinocandin MK-0991, formerly L-743,872, is a water-sol. lipopeptide that has been demonstrated in preclin. studies to have potent activity against Candida spp., Aspergillus fumigatus, and Pneumocystis carinii. An extensive in vitro biol. evaluation of MK-0991 was performed to better define the potential activities of this novel compd. Susceptibility testing with MK-0991 against approx. 200 clin. isolates of Candida, Cryptococcus neoformans, and Aspergillus isolates was conducted to det. MICs and min. fungicidal concns. MF(s). The MFC at which 90% of isolates are inhibited for 40 C. albicans clin. isolates was 0.5 μg/mL. Susceptibility testing with panels of antifungal agent-resistant species of Candida and C. neoformans isolates indicated that the MK-0991 MFCs for these isolates are comparable to those obtained for susceptible isolates. Growth kinetic studies of MK-0991 against Candida albicans and Candida tropicalis isolates showed that the compd. exhibited fungicidal activity (i.e., a 99% redn. in viability) within 3 to 7 h at concns. ranging from 0.06 to 1 μg/mL (0.25 to 4 times the MIC). Drug combination studies with MK-0991 plus amphotericin B found that this combination was not antagonistic against C. albicans, C. neoformans, or A. fumigatus in vitro. Studies with 0 to 50% pooled human or mouse serum established that fungal susceptibility to MK-0991 was not significantly influenced by the presence of human or mouse serum. Results from resistance induction studies suggested that the susceptibility for C. albicans was not altered by repeated exposure (40 passages) to MK-0991. Erythrocyte hemolysis studies with MK-0991 with washed and unwashed human or mouse erythrocytes indicated minimal hemolytic potential with this compd. These favorable results of preclin. studies support further studies with MK-0991 with humans.(b) Hajdu, R.; Thompson, R.; Sundelof, J. G.; Pelak, B. A.; Bouffard, F. A.; Dropinski, J. F.; Kropp, H. Preliminary animal pharmacokinetics of the parenteral antifungal agent MK-0991 (L-743,872). Antimicrob. Agents Chemother. 1997, 41, 2339– 2344, DOI: 10.1128/AAC.41.11.2339[Crossref], [PubMed], [CAS], Google Scholar274bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXntFKgu7k%253D&md5=b981d69499d0608b6c25270311384345Preliminary animal pharmacokinetics of the parenteral antifungal agent MK-0991 (L-743,872)Hajdu, Richard; Thompson, Randall; Sundelof, Jon G.; Pelak, Barbara A.; Bouffard, F. Aileen; Dropinski, James F.; Kropp, HelmutAntimicrobial Agents and Chemotherapy (1997), 41 (11), 2339-2344CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)MK-0991 (L-743,872) is a potent antifungal agent featuring long half-life pharmacokinetics. The pharmacokinetics of MK-0991 administered i.v. to mice, rats, rhesus monkeys, and chimpanzees is presented. Unique to MK-0991 is its consistent cross-species performance. The range of values for the pharmacokinetic parameters were as follows: clearance, 0.26 to 0.51 mL/min/kg; half-life, 5.2 to 7.6 h; and distributive vol., 0.11 to 0.27 L/kg. The level of protein binding of MK-0991 was detd. to be 96% in mouse and human serum. The compd. exhibited high affinities for human serum albumin and at least two lipid components. The rationale for the selection of MK-0991 as a drug development candidate was based on its two- to threefold superior pharmacokinetic performance in chimpanzees over the performance of an otherwise equiv. analog, L-733,560. Once-daily dosing for MK-0991 is indicated by a graphical comparison of levels in the circulations of chimpanzees and mice. In a study of the pharmacokinetics of MK-0991 in mouse tissue, the organs were assayed following i.p. administration. The area under the concn.-vs.-time curves (AUC) segregated the tissues into three exposure categories relative to plasma. The tissues with greater exposure than that for plasma were liver (16 times), kidney (3 times), and large intestine (2 times). The exposure for small intestine, lung, and spleen were equiv. to that for plasma. Organs with lower levels of exposure were the heart (0.3 times that for plasma), thigh (0.2 times), and brain (0.06 times). Kinetically, drug was cleared more slowly from all tissues than from plasma, indicating that terminal-phase equil. had not been achieved by 24 h. Thus, some measure of accumulation is predicted for all tissues. Single daily doses of MK-0991 should provide adequate systemic levels of fungicidal activity as a results of its long half-life pharmacokinetics, wide distribution, and slowly accumulating concns. in tissue.
- 275(a) Snyder, L. B.; Meng, Z.; Mate, R.; D’Andrea, S. V.; Marinier, A.; Quesnelle, C. A.; Gill, P.; DenBleyker, K. L.; Fung-Tomc, J. C.; Frosco, M.; Martel, A.; Barrett, J. F.; Bronson, J. J. Discovery of isoxazolinone antibacterial agents. Nitrogen as a replacement for the stereogenic center found in oxazolidinone antibacterials. Bioorg. Med. Chem. Lett. 2004, 14, 4735– 4739, DOI: 10.1016/j.bmcl.2004.06.076[Crossref], [PubMed], [CAS], Google Scholar.275ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXmvV2htL4%253D&md5=f54df1a32854d6244efacef632fb0e8cDiscovery of isoxazolinone antibacterial agents. Nitrogen as a replacement for the stereogenic center found in oxazolidinone antibacterialsSnyder, Lawrence B.; Meng, Zhaoxing; Mate, Robert; D'Andrea, Stanley V.; Marinier, Anne; Quesnelle, Claude A.; Gill, Patrice; DenBleyker, Kenneth L.; Fung-Tomc, Joan C.; Frosco, MaryBeth; Martel, Alain; Barrett, John F.; Bronson, Joanne J.Bioorganic & Medicinal Chemistry Letters (2004), 14 (18), 4735-4739CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A series of potential antimicrobial derivs. possessing bioisosteric replacements for the central oxazolidinone ring found in oxazolidinone antibacterials have been prepd. The design concept involved replacement of the requisite sp3-hybridized stereogenic center found at the 5-position of the oxazolidinone with a nitrogen atom. The synthesis and antibacterial activity of three such ring systems, the benzisoxazolinones, e.g., I, pyrroles, e.g., II, and isoxazolinones, e.g., III, is described.(b) Quesnelle, C. A.; Gill, P.; Roy, S.; Dodier, M.; Marinier, A.; Martel, A.; Snyder, L. B.; D’Andrea, S. V.; Bronson, J. J.; Frosco, M.; Beaulieu, D.; Warr, G. A.; DenBleyker, K. L.; Stickle, T. M.; Yang, H.; Chaniewski, S. E.; Ferraro, C. A.; Taylor, D.; Russell, J. W.; Santone, K. S.; Clarke, J.; Drain, R. L.; Knipe, J. O.; Mosure, K.; Barrett, J. F. Biaryl isoxazolinone antibacterial agents. Bioorg. Med. Chem. Lett. 2005, 15, 2728– 2733, DOI: 10.1016/j.bmcl.2005.04.003[Crossref], [PubMed], [CAS], Google Scholar275bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXks1Wjt7Y%253D&md5=1cff860acd12c136634ed19a5a39abbfBiaryl isoxazolinone antibacterial agentsQuesnelle, Claude A.; Gill, Patrice; Roy, Stephan; Dodier, Marco; Marinier, Anne; Martel, Alain; Snyder, Lawrence B.; D'Andrea, Stanley V.; Bronson, Joanne J.; Frosco, MaryBeth; Beaulieu, Danielle; Warr, Glen A.; DenBleyker, Ken L.; Stickle, Terry M.; Yang, Hyekyung; Chaniewski, Susan E.; Ferraro, Cheryl A.; Taylor, Dennis; Russell, John W.; Santone, Kenneth S.; Clarke, Junius; Drain, Rebecca L.; Knipe, Jay O.; Mosure, Kathleen; Barrett, John F.Bioorganic & Medicinal Chemistry Letters (2005), 15 (11), 2728-2733CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)In an era of increasing resistance to classical antibacterial agents, the synthetic oxazolidinone series of antibiotics has attracted much interest. Zyvox was the first oxazolidinone to be approved for clin. use against infections caused by multi-drug resistant Gram-pos. bacteria. In the course of studies directed toward the discovery of novel antibacterial agents, a new series of synthetic phenyl-isoxazolinone agents that displayed potent activity against Gram-pos. bacterial strains was recently discovered at Bristol-Myers Squibb. Extensive investigation of various substitutions on the Ph ring was then undertaken. We report here, the synthesis and antibacterial activity of a series of biaryl isoxazolinone compds. I (R = substituted Ph, 1-naphthyl, 2-pyridyl, 3-furyl, 4-tetrahydropyranyl, 4-pyridyl, etc.). Synthesis involved cross-coupling approaches.
- 276Kees, K. L.; Caggiano, T. J.; Steiner, K. E.; Fitzgerald, J. J., Jr.; Kates, M. J.; Christos, T. E.; Kulishoff, J. M., Jr.; Moore, R. D.; McCaleb, M. L. Studies on new acidic azoles as glucose-lowering agents in obese, diabetic db/db mice. J. Med. Chem. 1995, 38, 617– 628, DOI: 10.1021/jm00004a008[ACS Full Text], [CAS], Google Scholar276https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXjsFaisLs%253D&md5=967f2eb150cb5805338dc40b674d5683Studies on New Acidic Azoles as Glucose-Lowering Agents in Obese, Diabetic db/db MiceKees, Kenneth L.; Caggiano, Thomas J.; Steiner, Kurt E.; Fitzgerald, John J., Jr.; Kates, Michael J.; Christos, Thomas E.; Kulishoff, John M.; Moore, Robin D.; McCaleb, Michael L.Journal of Medicinal Chemistry (1995), 38 (4), 617-28CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Bioisosteric substitution was used as a tool to generate several new structural alternatives to the thiazolidine-2,4-dione and tetrazole heterocycles as potential antidiabetic agents. Among the initial leads that emerged from this strategy, a family of acidic azoles, isoxazol-3- and -5-ones and a pyrazol-3-one, showed significant plasma glucose-lowering activity (17-42% redn.) in genetically obese, diabetic db/db mice at a dose of 100 mg/kg/day ×4. Structure-activity relationship studies detd. that 5-alkyl-4-(arylmethyl)pyrazol-3-ones, which exist in soln. as arom. enol/iminol tautomers, were the most promising new class of potential antidiabetic agent (32-45% redn. at 20 mg/kg/d ×4). Included in this work are convenient syntheses for several types of acidic azoles that may find use as new acidic bioisosteres in medicinal chem. such as the antidiabetic lead 5-(trifluoromethyl)pyrazol-3-one, hydroxy tautomer, and aza homologs of the pyrazolones, 1,2,3-triazol-5-ones (hydroxy tautomer) and 1,2,3,4-tetrazol-5-one heterocycles. Log P and pKa data for 15 potential acidic bioisosteres, all appended to a 2-naphthalenylmethyl residue so as to maintain a similar distance between the acidic hydrogen and arene nucleus, are presented. This new data set allows comparison of a wide variety of potential acid mimetics (pKa 3.78-10.66; log P -0.21 to 2.76) for future drug design.
- 277(a) Noshi, T.; Kitano, M.; Taniguchi, K.; Yamamoto, A.; Omoto, S.; Baba, K.; Hashimoto, T.; Ishida, K.; Kushima, Y.; Hattori, K.; Kawai, M.; Yoshida, R.; Kobayashi, M.; Yoshinaga, T.; Sato, A.; Okamatsu, M.; Sakoda, Y.; Kida, H.; Shishido, T.; Naito, A. In vitro characterization of baloxavir acid, a first-in-class cap-dependent endonuclease inhibitor of the influenza virus polymerase PA subunit. Antiviral Res. 2018, 160, 109– 117, DOI: 10.1016/j.antiviral.2018.10.008[Crossref], [PubMed], [CAS], Google Scholar.277ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitVKhsbrL&md5=a7758d09b99a3b68221defe4c507838dIn vitro characterization of baloxavir acid, a first-in-class cap-dependent endonuclease inhibitor of the influenza virus polymerase PA subunitNoshi, Takeshi; Kitano, Mitsutaka; Taniguchi, Keiichi; Yamamoto, Atsuko; Omoto, Shinya; Baba, Keiko; Hashimoto, Takashi; Ishida, Kayo; Kushima, Yukihiro; Hattori, Kazunari; Kawai, Makoto; Yoshida, Ryu; Kobayashi, Masanori; Yoshinaga, Tomokazu; Sato, Akihiko; Okamatsu, Masatoshi; Sakoda, Yoshihiro; Kida, Hiroshi; Shishido, Takao; Naito, AkiraAntiviral Research (2018), 160 (), 109-117CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)Cap-dependent endonuclease (CEN) resides in the PA subunit of the influenza virus and mediates the crit. "cap-snatching" step of viral RNA transcription, which is considered to be a promising anti-influenza target. Here, we describe in vitro characterization of a novel CEN inhibitor, baloxavir acid (BXA), the active form of baloxavir marboxil (BXM). BXA inhibits viral RNA transcription via selective inhibition of CEN activity in enzymic assays, and inhibits viral replication in infected cells without cytotoxicity in cytopathic effect assays. The antiviral activity of BXA is also confirmed in yield redn. assays with seasonal type A and B viruses, including neuraminidase inhibitor-resistant strains. Furthermore, BXA shows broad potency against various subtypes of influenza A viruses (H1N2, H5N1, H5N2, H5N6, H7N9 and H9N2). Addnl., serial passages of the viruses in the presence of BXA result in isolation of PA/I38T variants with reduced BXA susceptibility. Phenotypic and genotypic analyses with reverse genetics demonstrate the mechanism of BXA action via CEN inhibition in infected cells. These results reveal the in vitro characteristics of BXA and support clin. use of BXM to treat influenza.(b) Miyagawa, M.; Akiyama, T.; Taoda, Y.; Takaya, K.; Takahashi-Kageyama, C.; Tomita, K.; Yasuo, K.; Hattori, K.; Shano, S.; Yoshida, R.; Shishido, T.; Yoshinaga, T.; Sato, A.; Kawai, M. Synthesis and SAR study of carbamoyl pyridone bicyclederivatives as potent inhibitors of influenza cap-dependent endonuclease. J. Med. Chem. 2019, 62, 8101– 8114, DOI: 10.1021/acs.jmedchem.9b00861[ACS Full Text], [CAS], Google Scholar277bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsFamsrrF&md5=73373f0232f87b3d5b685037612e8859Synthesis and SAR Study of Carbamoyl Pyridone Bicycle Derivatives as Potent Inhibitors of Influenza Cap-dependent EndonucleaseMiyagawa, Masayoshi; Akiyama, Toshiyuki; Taoda, Yoshiyuki; Takaya, Kenji; Takahashi-Kageyama, Chika; Tomita, Kenji; Yasuo, Kazuya; Hattori, Kazunari; Shano, Shinya; Yoshida, Ryu; Shishido, Takao; Yoshinaga, Tomokazu; Sato, Akihiko; Kawai, MakotoJournal of Medicinal Chemistry (2019), 62 (17), 8101-8114CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The medicinal chem. and structure-activity relationships (SAR) for a novel series of carbamoyl pyridone bicycle (CAB) compds. as influenza Cap-dependent endonuclease (CEN) inhibitors are disclosed. Substituent effects were evaluated at the C (N)-1, N-3, and C-7 positions of the CAB ring system using a docking study. Submicromolar EC50 values were achieved in the cellular assay with C-7-unsubstituted CAB which possessed a benzhydryl group on either the C-1 or the N-1 position. An N-3 substituent was found to be crit. for the plasma protein binding effect in vitro, and the CAB-N analog I exhibited reasonable total clearance (CLtot). More importantly, compd. I displayed significant efficacy in a mouse model infected with influenza viruses.
- 278Taoda, Y.; Miyagawa, M.; Akiyama, T.; Tomita, K.; Hasegawa, Y.; Yoshida, R.; Noshi, T.; Shishido, T.; Kawai, M. Dihydrodibenzothiepine: promising hydrophobic pharmacophore in the influenza cap-dependent endonuclease inhibitor. Bioorg. Med. Chem. Lett. 2020, 30, 127547, DOI: 10.1016/j.bmcl.2020.127547[Crossref], [PubMed], [CAS], Google Scholar278https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhvV2ntLzK&md5=5e935bf21cd2a6dfd9a8daf315111a84Dihydrodibenzothiepine: Promising hydrophobic pharmacophore in the influenza cap-dependent endonuclease inhibitorTaoda, Yoshiyuki; Miyagawa, Masayoshi; Akiyama, Toshiyuki; Tomita, Kenji; Hasegawa, Yasushi; Yoshida, Ryu; Noshi, Takeshi; Shishido, Takao; Kawai, MakotoBioorganic & Medicinal Chemistry Letters (2020), 30 (22), 127547CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)This work describes a set of discovery research studies of an influenza cap-dependent endonuclease (CEN) inhibitors with a carbamoyl pyridone bicycle (CAB) scaffold, particularly dibenzothiepine-substituted pyridotriazinediones such as I. Using influenza CEN inhibitory activity, antiviral activity and pharmacokinetic (PK) parameters as indexes, structure activity relationships (SAR) studies were performed at the N-1 and N-3 positions on the CAB scaffold, which is a unique template to bind two metals. The hydrophobic substituent at the N-1 position is extremely important for CEN inhibitory activity and antiviral activity, and dihydrodibenzothiepine was the most promising pharmacophore. I showed potent virus titer redn. over oseltamivir phosphate in an in vivo mouse model. I served as the lead compd. of baloxavir marboxil with a tricyclic scaffold, which was approved in Japan and the USA in 2018.
- 279(a) Heo, Y.-A. Baloxavir: first global approval. Drugs 2018, 78, 693– 697, DOI: 10.1007/s40265-018-0899-1[Crossref], [PubMed], [CAS], Google Scholar.279ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXnsVejsr0%253D&md5=1b11d92b5dc5807b6de1d1920ed1e4e5Baloxavir: First Global ApprovalHeo, Young-A.Drugs (2018), 78 (6), 693-697CODEN: DRUGAY; ISSN:0012-6667. (Springer International Publishing AG)Baloxavir marboxil (Xofluza; baloxavir) is an oral cap-dependent endonuclease inhibitor that has been developed by Roche and Shionogi. The drug blocks influenza virus proliferation by inhibiting the initiation of mRNA synthesis. In Feb. 2018, baloxavir received its first global approval in Japan for the treatment of influenza A or B virus infections. Phase III development is underway in the USA, EU and other countries for this indication. This article summarized the milestones in the development of baloxavir leading to this first global approval for influenza A or B virus infections.(b) Shirley, M. Baloxavir marboxil: a review in acute uncomplicated influenza. Drugs 2020, 80, 1109– 1118, DOI: 10.1007/s40265-020-01350-8[Crossref], [PubMed], [CAS], Google Scholar279bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtlWgurbK&md5=84f34ff0b87aea5756502ba18e010c26Baloxavir Marboxil: A Review in Acute Uncomplicated InfluenzaShirley, MattDrugs (2020), 80 (11), 1109-1118CODEN: DRUGAY; ISSN:0012-6667. (Springer International Publishing AG)A review. Abstr.: Baloxavir marboxil (Xofluza; hereafter referred to as baloxavir), the prodrug of baloxavir acid, is a first-in-class, small mol. inhibitor of the polymerase acidic (PA) protein subunit of the influenza virus polymerase complex. Baloxavir (after conversion to baloxavir acid) acts to block influenza virus replication by inhibiting the cap-dependent endonuclease activity of the PA protein. Taken orally as a single dose, baloxavir is approved in the USA for the treatment of acute uncomplicated influenza in patients ≥ 12 years of age who have been symptomatic for ≤ 48 h. Data from randomized, double-blind, placebo- and oseltamivir-controlled phase III trials have shown that baloxavir is efficacious in improving influenza symptoms both in otherwise healthy adolescents and adults and in those at high risk of influenza complications, displaying similar efficacy to that of oseltamivir. Furthermore, there is evidence that baloxavir can reduce influenza viral load more rapidly than oseltamivir. Baloxavir has activity against influenza A and B viruses (including strains resistant to neuraminidase inhibitors) and is well tolerated. Evidence of the emergence and likely human-to-human transmission of variant viruses with reduced susceptibility to baloxavir highlights the importance of monitoring and surveillance for changes in influenza virus drug susceptibility patterns. However, currently available evidence suggests that baloxavir, with the benefits of a single oral dose regimen, provides a useful alternative to neuraminidase inhibitors for the treatment of acute uncomplicated influenza in adolescents and adults.
- 280Raheem, I. T.; Walji, A. M.; Klein, D.; Sanders, J. M.; Powell, D. A.; Abeywickrema, P.; Barbe, G.; Bennet, A.; Clas, S.; Dubost, D.; Embrey, M.; Grobler, J.; Hafey, M. J.; Hartingh, T. J.; Hazuda, D. J.; Miller, M. D.; Moore, K. P.; Pajkovic, N.; Patel, S.; Rada, V.; Rearden, P.; Schreier, J. D.; Sisko, J.; Steele, T. G.; Truchon, J.; Wai, J.; Xu, M.; Coleman, P. J. Discovery of 2-pyridinone aminals: a prodrug strategy to advance a second generation of HIV-1 integrase strand transfer inhibitors. J. Med. Chem. 2015, 58, 8154– 8165, DOI: 10.1021/acs.jmedchem.5b01037[ACS Full Text], [CAS], Google Scholar280https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsFersrvJ&md5=bec0c2f7710a1e4e8cc3a502067a2236Discovery of 2-Pyridinone Aminals: A Prodrug Strategy to Advance a Second Generation of HIV-1 Integrase Strand Transfer InhibitorsRaheem, Izzat T.; Walji, Abbas M.; Klein, Daniel; Sanders, John M.; Powell, David A.; Abeywickrema, Pravien; Barbe, Guillaume; Bennet, Amrith; Childers, Karla; Christensen, Melodie; Clas, Sophie-Dorothee; Dubost, David; Embrey, Mark; Grobler, Jay; Hafey, Michael J.; Hartingh, Timothy J.; Hazuda, Daria J.; Kuethe, Jeffrey T.; Dunn, Jamie McCabe; Miller, Michael D.; Moore, Keith P.; Nolting, Andrew; Pajkovic, Natasa; Patel, Sangita; Peng, Zuihui; Rada, Vanessa; Rearden, Paul; Schreier, John D.; Sisko, John; Steele, Thomas G.; Truchon, Jean-Francois; Wai, John; Xu, Min; Coleman, Paul J.Journal of Medicinal Chemistry (2015), 58 (20), 8154-8165CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The search for new mol. constructs that resemble the crit. two-metal binding pharmacophore required for HIV integrase strand transfer inhibition represents a vibrant area of research within drug discovery. Here the authors present the discovery of a new class of HIV integrase strand transfer inhibitors based on the 2-pyridinone core of MK-0536. These efforts led to the identification of two lead compds. I and II with excellent antiviral activity and preclin. pharmacokinetic profiles to support a once-daily human dose prediction. Dose escalating PK studies in dog revealed significant issues with limited oral absorption and required an innovative prodrug strategy to enhance the high-dose plasma exposures of the parent mols.
- 281Reich, S. H.; Sprengeler, P. A.; Chiang, G. G.; Appleman, J. R.; Chen, J.; Clarine, J.; Eam, B.; Ernst, J. T.; Han, Q.; Goel, V. K.; Han, E.; Huang, V.; Hung, I.; Jemison, A.; Jessen, K. A.; Molter, J.; Murphy, D.; Neal, M.; Parker, G. S.; Shaghafi, M.; Sperry, S.; Staunton, J.; Stumpf, C. R.; Thompson, P. A.; Tran, C.; Webber, S. E.; Wegerski, C. J.; Zheng, H.; Webster, K. R. Structure-based design of pyridone-aminal eFT508 targeting dysregulated translation by selective mitogen-activated protein kinase interacting kinases 1 and 2 (MNK1/2) inhibition. J. Med. Chem. 2018, 61, 3516– 3540, DOI: 10.1021/acs.jmedchem.7b01795[ACS Full Text], [CAS], Google Scholar281https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXktlGhs7s%253D&md5=1254b674aa7e6d2037a06bc10e64e4daStructure-based Design of Pyridone-Aminal eFT508 Targeting Dysregulated Translation by Selective Mitogen-activated Protein Kinase Interacting Kinases 1 and 2 (MNK1/2) InhibitionReich, Siegfried H.; Sprengeler, Paul A.; Chiang, Gary G.; Appleman, James R.; Chen, Joan; Clarine, Jeff; Eam, Boreth; Ernst, Justin T.; Han, Qing; Goel, Vikas K.; Han, Edward Z. R.; Huang, Vera; Hung, Ivy N. J.; Jemison, Adrianna; Jessen, Katti A.; Molter, Jolene; Murphy, Douglas; Neal, Melissa; Parker, Gregory S.; Shaghafi, Michael; Sperry, Samuel; Staunton, Jocelyn; Stumpf, Craig R.; Thompson, Peggy A.; Tran, Chinh; Webber, Stephen E.; Wegerski, Christopher J.; Zheng, Hong; Webster, Kevin R.Journal of Medicinal Chemistry (2018), 61 (8), 3516-3540CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Dysregulated translation of mRNA plays a major role in tumorigenesis. Mitogen-activated protein kinase interacting kinases (MNK)1/2 are key regulators of mRNA translation integrating signals from oncogenic and immune signaling pathways through phosphorylation of eIF4E and other mRNA binding proteins. Modulation of these key effector proteins regulates mRNA, which controls tumor/stromal cell signaling. Compd. 23 (eFT508, 6'-((6-aminopyrimidin-4-yl)amino)-8'-methyl-2'H-spiro-[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione hydrochloride), an exquisitely selective, potent dual MNK1/2 inhibitor, was designed to assess the potential for control of oncogene signaling at the level of mRNA translation. The crystal structure-guided design leverages stereoelectronic interactions unique to MNK culminating in a novel pyridone-aminal structure described for the first time in the kinase literature. Compd. 23 has potent in vivo antitumor activity in models of diffuse large cell B-cell lymphoma and solid tumors, suggesting that controlling dysregulated translation has real therapeutic potential. Compd. 23 is currently being evaluated in Phase 2 clin. trials in solid tumors and lymphoma. Compd. 23 is the first highly selective dual MNK inhibitor targeting dysregulated translation being assessed clin.
- 282Paulini, R.; Laus Müller, K.; Diederich, F. Orthogonal multipolar interactions in structural chemistry and biology. Angew. Chem., Int. Ed. 2005, 44, 1788– 1805, DOI: 10.1002/anie.200462213[Crossref], [CAS], Google Scholar282https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXislWkt7s%253D&md5=6ad842547313b27fc1676e9c3a001909Orthogonal multipolar interactions in structural chemistry and biologyPaulini, Ralph; Mueller, Klaus; Diederich, FrancoisAngewandte Chemie, International Edition (2005), 44 (12), 1788-1805CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. The past few decades of mol. recognition studies have greatly enhanced our knowledge on apolar, ion-dipole, and hydrogen-bonding interactions. However, much less attention has been given to the role that multipolar interactions, in particular those with orthogonal dipolar alignment, play in organizing a crystal lattice or stabilizing complexes involving biol. receptors. By using results from database mining, this review attempts to give an overview of types and structural features of these previously rather overlooked interactions. A no. of illustrative examples of these interactions found in X-ray crystal structures of small mols. and protein-ligand complexes demonstrate their propensity and thus potential importance for both, chem. and biol. mol. recognition processes.
- 283A study to evaluate the efficacy and safety of TAK-906 in adult participants with symptomatic idiopathic or diabetic gastroparesis. https://clinicaltrials.gov/ct2/show/NCT03544229 (accessed April 29, 2021).
- 284Whiting, R. L.; Darpo, B.; Chen, C.; Fletcher, M.; Combs, D.; Xue, H.; Stoltz, R. R. Safety, pharmacokinetics, and pharmacodynamics of trazpiroben (TAK-906), a novel selective D2/D3 receptor antagonist: a Phase 1 randomized, placebo-controlled single- and multiple-dose escalation study in healthy participants. Clin. Pharmacol. Drug Dev. 2021, in press. DOI: 10.1002/cpdd.906 . Epub ahead of print. PMID: 33462988.
- 285A study to evaluate the safety and efficacy of NG101 in adult participants with symptomatic diabetic or idiopathic gastroparesis. https://clinicaltrials.gov/ct2/show/NCT04303195 (accessed April 29, 2021).
- 286Nishihara, M.; Ramsden, D.; Balani, S. K. Evaluation of the drug-drug interaction potential for trazpiroben (TAK-906), a D2/D3 receptor antagonist for gastroparesis, towards cytochrome P450s and transporters. Xenobiotica 2021 in press. 51 668 DOI: 10.1080/00498254.2021.1912438 .[Crossref], [PubMed], [CAS], Google Scholar286https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXptFyrsLo%253D&md5=83ebdee86cd6ffeafb8aceef24a89091Evaluation of the drug-drug interaction potential for trazpiroben (TAK-906), a D2/D3 receptor antagonist for gastroparesis, towards cytochrome P450s and transportersNishihara, Mitsuhiro; Ramsden, Diane; Balani, Suresh K.Xenobiotica (2021), 51 (6), 668-679CODEN: XENOBH; ISSN:0049-8254. (Taylor & Francis Ltd.)Trazpiroben (TAK-906), a peripherally selective dopamine D2/D3 receptor antagonist, is being developed for the treatment of patients with gastroparesis. The potential of trazpiroben to act as a perpetrator or a victim for cytochrome P 450 (CYP)- or transporter- mediated drug-drug interactions (DDIs) was evaluated following the latest regulatory guidelines. In vitro studies revealed that trazpiroben is metabolised mainly through a non-CYP pathway (56.7%) by multiple cytosolic, NADPH-dependent reductase, such as aldo-keto reductase and short-chain dehydrogenase/reductase including carbonyl reductases. Remaining metab. occurs through CYP3A4 and CYP2C8 (43.3%). Trazpiroben is neither an inhibitor nor an inducer of major CYP enzymes at a clin. relevant dose. It is a substrate of P-glycoprotein (P-gp) and org. anion transporting polypeptide (OATP) 1B1/1B3, but is not an inhibitor of transporters listed in the DDI guidelines at a clin. relevant dose. This is consistent with findings from CYP3A and P-gp-based clin. assessment showing no substantial change (≤2-fold) in trazpiroben exposure when co-administered with itraconazole. Collectively, trazpiroben has low potential of enzyme-mediated DDIs and is unlikely to act as a perpetrator of transporter-mediated DDIs but there may be a potential to act as a victim of OATP1B1/1B3 DDI that will be evaluated clin.
- 287(a) Bond, S.; Draffan, A. G.; Fenner, J. E.; Lambert, J.; Lim, C. Y.; Lin, B.; Luttick, A.; Mitchell, J. P.; Morton, C. J.; Nearn, R. H.; Sanford, V.; Stanislawski, P. C.; Tucker, S. P. The discovery of 1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-ones as a new class of respiratory syncytial virus (RSV) fusion inhibitors. Part 1. Bioorg. Med. Chem. Lett. 2015, 25, 969– 975, DOI: 10.1016/j.bmcl.2014.11.018[Crossref], [PubMed], [CAS], Google Scholar.287ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvFGis7rO&md5=3c21eca5a14547d10972c182d4c89c80The discovery of 1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-ones as a new class of respiratory syncytial virus (RSV) fusion inhibitors. Part 1Bond, Silas; Draffan, Alistair G.; Fenner, Jennifer E.; Lambert, John; Lim, Chin Yu; Lin, Bo; Luttick, Angela; Mitchell, Jeffrey P.; Morton, Craig J.; Nearn, Roland H.; Sanford, Vanessa; Stanislawski, Pauline C.; Tucker, Simon P.Bioorganic & Medicinal Chemistry Letters (2015), 25 (4), 969-975CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Respiratory syncytial virus (RSV) is a major cause of respiratory tract infections in infants, young children and adults. Compd. 1a (9b-(4-chlorophenyl)-1-(4-fluorobenzoyl)-1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-one) was identified as an inhibitor of A and B strains of RSV targeting the fusion glycoprotein. SAR was developed by systematic exploration of the Ph (R1) and benzoyl (R2) groups. Furthermore, introduction of a nitrogen at the 8-position of the tricyclic core resulted in active analogs with improved properties (aq. soly., protein binding and log D) and excellent rat pharmacokinetics (e.g., rat oral bioavailability of 89% for compd. 17, I).(b) Bond, S.; Draffan, A. G.; Fenner, J. E.; Lambert, J.; Lim, C. Y.; Lin, B.; Luttick, A.; Mitchell, J. P.; Morton, C. J.; Nearn, R. H.; Sanford, V.; Anderson, K. H.; Mayes, P. A.; Tucker, S. P. 1,2,3,9b-Tetrahydro-5H-imidazo[2,1-a]isoindol-5-ones as a new class of respiratory syncytial virus (RSV) fusion inhibitors. Part 2: Identification of BTA9881 as a preclinical candidate. Bioorg. Med. Chem. Lett. 2015, 25, 976– 981, DOI: 10.1016/j.bmcl.2014.11.024[Crossref], [PubMed], [CAS], Google Scholar287bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvFGis7rN&md5=6a0df66bad0f8c19627d2cf31bccca611,2,3,9b-Tetrahydro-5H-imidazo[2,1-a]isoindol-5-ones as a new class of respiratory syncytial virus (RSV) fusion inhibitors. Part 2: Identification of BTA9881 as a preclinical candidateBond, Silas; Draffan, Alistair G.; Fenner, Jennifer E.; Lambert, John; Lim, Chin Yu; Lin, Bo; Luttick, Angela; Mitchell, Jeffrey P.; Morton, Craig J.; Nearn, Roland H.; Sanford, Vanessa; Anderson, Kelly H.; Mayes, Penelope A.; Tucker, Simon P.Bioorganic & Medicinal Chemistry Letters (2015), 25 (4), 976-981CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Respiratory syncytial virus (RSV) is a major cause of respiratory tract infections in infants, young children and adults. 1,2,3,9b-Tetrahydro-5H-imidazo[2,1-a]isoindol-5-ones with general structure 1 were previously identified as promising inhibitors of RSV targeting the fusion glycoprotein. In particular, the introduction of a nitrogen at the 8-position of the tricyclic core yielded lead compds. Extensive exploration of the R2 group established that certain heterocyclic amides conferred potent RSV A&B activity and a good balance of physicochem. and pharmacokinetic properties. The antiviral activity was found to reside in a single enantiomer and BTA9881 (I) was identified as a candidate for preclin. development.
- 288Gentry, P. R.; Kokubo, M.; Bridges, T. M.; Kett, N. R.; Harp, J. M.; Cho, H. P.; Smith, E.; Chase, P.; Hodder, P. S.; Niswender, C. M.; Daniels, J. S.; Conn, P. J.; Wood, M. R.; Lindsley, C. M. Discovery of the first M5-selective and CNS penetrant negative allosteric modulator (NAM) of a muscarinic acetylcholine receptor: (S)-9b-(4-chlorophenyl)-1-(3,4-difluorobenzoyl)-2,3-dihydro-1H-imidazo[2,1-a]isoindol-5(9bH)-one (ML375). J. Med. Chem. 2013, 56, 9351– 9355, DOI: 10.1021/jm4013246[ACS Full Text], [CAS], Google Scholar288https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhs1ylsLzN&md5=fd5f4e5155d57ddb882bd68b0544be4eDiscovery of the First M5 Selective and CNS Penetrant Negative Allosteric Modulator (NAM) of a Muscarinic Acetylcholine Receptor: (S) 9b-(4-Chlorophenyl)-1-(3,4-difluorobenzoyl)-2,3-dihydro 1H imidazo[2,1a]isoindol-5(9bH)one (ML375)Gentry, Patrick R.; Kokubo, Masaya; Bridges, Thomas M.; Kett, Nathan R.; Harp, Joel M.; Cho, Hyekyung P.; Smith, Emery; Chase, Peter; Hodder, Peter S.; Niswender, Colleen M.; Daniels, J. Scott; Conn, P. Jeffrey; Wood, Michael R.; Lindsley, Craig W.Journal of Medicinal Chemistry (2013), 56 (22), 9351-9355CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A functional high throughput screen and subsequent multidimensional, iterative parallel synthesis effort identified the first muscarinic acetylcholine receptor (mAChR) neg. allosteric modulator (NAM) selective for the M5 subtype. ML375 is a highly selective M5 NAM with submicromolar potency (human M5 IC50 = 300 nM, rat M5 IC50 = 790 nM, M1-M4 IC50 > 30 μM), excellent multispecies PK, high CNS penetration, and enantiospecific inhibition.
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Abstract
Figure 1
Figure 1. Structural elements with two heteroatoms, either oxygen, nitrogen, or sulfur or combinations thereof bound to a single sp3 carbon atom that have been exploited in drug design.
Figure 2
Figure 2. Naturally occurring polymers with nucleic acid oligomers and polysaccharides dependent upon geminal diheteroatomic linkages (marked in red), while polypeptides rely upon amide bonds for concatenation.
Figure 3
Figure 3. Select naturally occurring compounds 1–19 that incorporate geminal diheteroatomic motifs, which are marked in red.
Figure 4
Figure 4. Geminal diheteroatomic motifs that are present in marketed oral drugs, which are highlighted in red.
Scheme 1
Scheme 1. Mechanism of Hydrolysis of Ketals and AcetalsScheme 2
Scheme 2. Metabolism of Doxofylline (64)Scheme 3
Scheme 3. Metabolism of the Benzodioxole Moiety Leading to CYP Enzyme Inhibition and the Production of Catechol and ortho-QuinoneScheme 4
Scheme 4. Potential Pathway for the Acid-Catalyzed Degradation of [1,3]Dioxolo[4,5-c]pyridine 100Scheme 5
Scheme 5. Condensation of an Amino Acid-Derived Aldehyde 119 with a Tartaric Acid 120 to Afford 3-Aza-6,8-dioxabicyclo[3.2.1]octanes 121 and Their Reduction to Amines 122Scheme 6
Scheme 6. Structure of 133 and Its Chemical Degradation and Metabolic PathwaysScheme 7
Scheme 7. Structure of 143, Its Evolution to 144 and 90, and Metabolism of 144Scheme 8
Scheme 8. Metabolism of 150 to Afford 160Scheme 9
Scheme 9. Metabolism of Phlorizin (172) to Phloretin (173) in VivoScheme 10
Scheme 10. Metabolism of 174 to the Glucoside 175 in VivoScheme 11
Scheme 11. Proposed Mechanism for the Hydrolysis of 188 at High pH ValuesScheme 12
Scheme 12. Potential Hydrolytic Degradation Pathways for 197Scheme 13
Scheme 13. Metabolic Pathways for 202Scheme 14
Scheme 14. Acid-Mediated Degradation of 169Figure 5
Figure 5. A. Key H-bonding interactions between 21 and the NK1 receptor. B. Conformation of 21 bound to the NK1 receptor. C. Single-crystal X-ray structure of 21 (GOPDUK, deposition number 117932 in the CSD).(114c,d)
Figure 6
Figure 6. Single-crystal X-ray structure of 218 (QESQIR, deposition number 1817710 in the CSD).(116d)
Figure 7
Figure 8
Figure 8. 1H NMR data for the substituted dioxanes 281a/b.
Scheme 15
Scheme 15. Acid-Catalyzed Degradation of 282 to afford 285 and the N-Dealkylation Metabolic Pathway Observed in Rats and Dogs to Afford 286 and 287Figure 9
Figure 9. Design principles that led to the discovery of 290.
Figure 10
Figure 10. Structure of the 5-LO inhibitor 295, metabolic pathways and structural evolution.
Figure 11
Figure 11. Design principle subtending the discovery of the core bicyclic ring system found in tofogliflozin (314).
Figure 12
Figure 12. Conformations available to 1,7-dioxaspiro[5.5]undecane (315).
Figure 13
Figure 13. Structure of HIV-1 protease inhibitor 321 depicting key intermolecular H-bonding interactions and evolution to bicyclic ethers.
Figure 14
Figure 14. Depiction of the anomeric effect in 195.
Scheme 16
Scheme 16. Potential Modes of Action of 195 Relying upon Iron-Catalyzed Degradation to Oxygen- or Carbon-Based RadicalsFigure 15
Figure 15. Depiction of the anomeric effects in 1,2,4-trioxolane 365, 1,2,4-troxane 361, and tetraoxane 366.
Scheme 17
Scheme 17. Degradation of 372–373 and Aldehyde 374Scheme 18
Scheme 18. Mechanism of Acid-Catalyzed (N,O)-Aminal HydrolysisFigure 16
Figure 16. Structures and chemical stability under acidic conditions of pseudoproline derivatives.
Figure 17
Figure 17. Structures and evolution of HCV NS5A inhibitors.
Scheme 19
Scheme 19. Proposed Mechanism of Inactivation of Serine-Containing β-Lactamase Enzymes by 393Figure 18
Figure 18. Structures and degradation pathways of 403 and 404.
Figure 19
Figure 19. Principle behind the design and synthesis of the HIV-1 integrase inhibitor 407.
Scheme 20
Scheme 20. Design of 413 and the Synthetic Approach Developed to Access the Core Molecule 418Figure 20
Figure 20. Design principle behind the discovery of 421.
Figure 21
Figure 21. Structure of the carboxonium (carbonylonium) ion intermediate that would be formed if 426 hydrolyzed by loss of the amine substituent.
Scheme 21
Scheme 21. Degradation Pathway for 438 Involving the Departure of the Phenol Moiety, A Process That Is Disfavored Electronically and by the Introduction of Strain in the Azetidinone RingScheme 22
Scheme 22. A1 Mechanism of Acid-Catalyzed Hydrolysis of NucleosidesScheme 23
Scheme 23. Degradation and Metabolism of 447Scheme 24
Scheme 24. Intracellular Metabolism of 458Scheme 25
Scheme 25. Hydrolysis of 2′-F-ara-ddI and 2′-F-ara-ddA Disfavored by the Presence of the 2′-F Atom, Which Destabilizes the Oxocarbenium Ion IntermediateScheme 26
Scheme 26. Metabolism of 466 and 467Figure 22
Figure 22. Evolutionary path from 472–477.
Scheme 27
Scheme 27. Structure of 480 and Its Intracellular Metabolic Pathway to the Active Triphosphate 482Scheme 28
Scheme 28. Proposed Decomposition Pathway for 2′,3′-Dideoxy, 2′3′-Didehydro Nucleoside AnaloguesScheme 29
Scheme 29. Acid-Catalyzed Decomposition Pathway for (O,S)-Acetals and Kinetic Data for Hydrolytic DegradationScheme 30
Scheme 30. Decomposition of 504 and Reassembly to Give 507 and Diol 508Scheme 31
Scheme 31. Mechanism of the Acid-Catalyzed Hydrolysis of ThioketalsScheme 32
Scheme 32. Metabolism of 526 in RLMScheme 33
Scheme 33. Mechanism of the Acid-Catalyzed Hydrolysis of (N,S)- (A) and (N,O)-Ketals (B)Scheme 34
Scheme 34. Hydrolysis of 536–537 and Structure of the Stable Analogue 538Scheme 35
Scheme 35. Metabolism of 540Scheme 36
Scheme 36. Mechanism of β-Lactamase Inhibition by 554Scheme 37
Scheme 37. (A) Mechanism of β-Lactamase Inhibition by 557; (B) Reaction of 561 with MethoxideScheme 38
Scheme 38. Mechanism of the Acid-Catalyzed Hydrolysis of (N,N)-AminalsScheme 39
Scheme 39. Decomposition of 583 into 585Scheme 40
Scheme 40. Structure of 586 and Degradation Pathways under Basic and Acidic ConditionsFigure 23
Figure 23. (A) The Bürgi–Dunitz angle for the approach of a nucleophile to the carbon atom of a carbonyl moiety; (B) details surrounding the interaction of the thiol of Cys225 with 610; (C) details associated with the interaction of the thiol of Cys225 with 612.
References
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Carbohydrates are a relatively untapped source of new drugs and therefore offer exciting new therapeutic opportunities. Advances in the functional understanding of carbohydrate-protein interactions have enabled the development of a new class of small-mol. drugs, known as glycomimetics. These compds. mimic the bioactive function of carbohydrates and address the drawbacks of carbohydrate leads, namely their low activity and insufficient drug-like properties. Here, we examine examples of approved carbohydrate-derived drugs, discuss the potential of carbohydrate-binding proteins as new drug targets (focusing on the lectin families) and consider ways to overcome the challenges of developing this unique class of novel therapeutics.(c) Galan, M. C.; Benito-Alifonso, D.; Watt, G. M. Carbohydrate chemistry in drug discovery. Org. Biomol. Chem. 2011, 9, 3598– 3610, DOI: 10.1039/c0ob01017k[Crossref], [PubMed], [CAS], Google Scholar5chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXlt1Ghsrs%253D&md5=a8b284b279adf59ab9b77b4d64b74460Carbohydrate chemistry in drug discoveryGalan, M. Carmen; Benito-Alifonso, David; Watt, Gregory M.Organic & Biomolecular Chemistry (2011), 9 (10), 3598-3610CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)A review. The multitude of roles that carbohydrates and their glyco-conjugates play in biol. processes has stimulated great interest in detg. the nature of their interactions in both normal and diseased states. Manipulating such interactions will provide leads for drug discovery. Of the major classes of biomol., carbohydrates are the most structurally diverse. This hetereogeneity makes isolation of pure samples, and in sufficient amts., from biol. sources extremely difficult. Chem. synthesis offers the advantage of producing pure and structurally defined oligosaccharides for biol. investigations. Although the complex nature of carbohydrates means that this is challenging, recent advances in the field have facilitated access to these mols. The synthesis and isolation of oligosaccharides combined with progress in glycoarray technol. have aided the identification of new carbohydrate-binding drug targets. This review aims to provide an overview of the latest advancements in carbohydrate chem. and the role of these complex mols. in drug discovery, focusing particularly on synthetic methodologies, glycosaminoglycans, glycoprotein synthesis and vaccine development over the last few years.
- 6Wolfenden, R. Benchmark reaction rates, the stability of biological molecules in water, and the evolution of catalytic power in enzymes. Annu. Rev. Biochem. 2011, 80, 645– 667, DOI: 10.1146/annurev-biochem-060409-093051[Crossref], [PubMed], [CAS], Google Scholar6https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXptVCnsbo%253D&md5=6aaaa405a1b4057ffaddf5c50fc975a8Benchmark reaction rates, the stability of biological molecules in water, and the evolution of catalytic power in enzymesWolfenden, RichardAnnual Review of Biochemistry (2011), 80 (), 645-667CODEN: ARBOAW; ISSN:0066-4154. (Annual Reviews Inc.)A review. The rates of enzyme reactions fall within a relatively narrow range. To est. the rate enhancements produced by enzymes, and their expected affinities for transition state analog inhibitors, it is necessary to measure the rates of the corresponding reactions in water in the absence of a catalyst. This review describes the spontaneous cleavages of C-C, C-H, C-N, C-O, P-O, and S-O bonds in biol. mols., as well as the uncatalyzed reactions that correspond to phosphoryl transfer reactions catalyzed by kinases and to peptidyl transfer in the ribosome. The rates of these reactions, some with half-lives in excess of one million years, span an overall range of 1019-fold. Moreover, the slowest reactions tend to be most sensitive to temp., with rates that increase as much as 107-fold when the temp. is raised from 25° to 100°C. That tendency collapses, by many orders of magnitude, the time that would have been required for chem. evolution on a warm earth. If the catalytic effect of primitive enzymes, like that of modern enzymes and many nonenzymic catalysts, were mainly to reduce a reaction's enthalpy of activation, then the resulting rate enhancement would have increased automatically as the surroundings cooled. By reducing the time required for early chem. evolution in a warm environment, these findings counter the view that not enough time has passed for terrestrial life to have evolved to its present level of complexity.
- 7(a) Beard, W. A.; Horton, J. K.; Prasad, R.; Wilson, S. H. Eukaryotic base excision repair: new approaches shine light on mechanism. Annu. Rev. Biochem. 2019, 88, 137– 162, DOI: 10.1146/annurev-biochem-013118-111315[Crossref], [PubMed], [CAS], Google Scholar.7ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXht1Wqt7rF&md5=08104c2a8791d94b37f3bf5e091bec9dEukaryotic Base Excision Repair: New Approaches Shine Light on MechanismBeard, William A.; Horton, Julie K.; Prasad, Rajendra; Wilson, Samuel H.Annual Review of Biochemistry (2019), 88 (), 137-162CODEN: ARBOAW; ISSN:0066-4154. (Annual Reviews)A review. Genomic DNA is susceptible to endogenous and environmental stresses that modify DNA structure and its coding potential. Correspondingly, cells have evolved intricate DNA repair systems to deter changes to their genetic material. Base excision DNA repair involves a no. of enzymes and protein cofactors that hasten repair of damaged DNA bases. Recent advances have identified macromol. complexes that assemble at the DNA lesion and mediate repair. The repair of base lesions generally requires five enzymic activities: glycosylase, endonuclease, lyase, polymerase, and ligase. The protein cofactors and mechanisms for coordinating the sequential enzymic steps of repair are being revealed through a range of exptl. approaches. We discuss the enzymes and protein cofactors involved in eukaryotic base excision repair, emphasizing the challenge of integrating findings from multiple methodologies. The results provide an opportunity to assimilate biochem. findings with cell-based assays to uncover new insights into this deceptively complex repair pathway.(b) Drohat, A. C.; Maiti, A. Mechanisms for enzymatic cleavage of the N-glycosidic bond in DNA. Org. Biomol. Chem. 2014, 12, 8367– 8378, DOI: 10.1039/C4OB01063A[Crossref], [PubMed], [CAS], Google Scholar7bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtlOlsbbO&md5=f95f28fcda9f87eba5d9911c368196edMechanisms for enzymatic cleavage of the N-glycosidic bond in DNADrohat, Alexander C.; Maiti, AtanuOrganic & Biomolecular Chemistry (2014), 12 (42), 8367-8378CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)A review. DNA glycosylases remove damaged or enzymically modified nucleobases from DNA, thereby initiating the base excision repair (BER) pathway, which is found in all forms of life. These ubiquitous enzymes promote genomic integrity by initiating repair of mutagenic and/or cytotoxic lesions that arise continuously due to alkylation, deamination, or oxidn. of the normal bases in DNA. DNA glycosylases also perform essential roles in epigenetic regulation of gene expression, by targeting enzymically-modified forms of the canonical DNA bases. Monofunctional DNA glycosylases hydrolyze the N-glycosidic bond to liberate the target base, while bifunctional glycosylases mediate glycosyl transfer using an amine group of the enzyme, generating a Schiff base intermediate that facilitates their 2nd activity, cleavage of the DNA backbone. Here, the authors review recent advances in understanding the chem. mechanism of monofunctional DNA glycosylases, with an emphasis on how the reactions are influenced by the properties of the nucleobase leaving-group, the moiety that varies across the vast range of substrates targeted by these enzymes.
- 8Vocadlo, D. J.; Davies, S. G. Mechanistic insights into glycosidase chemistry. Curr. Opin. Chem. Biol. 2008, 12, 539– 555, DOI: 10.1016/j.cbpa.2008.05.010[Crossref], [PubMed], [CAS], Google Scholar8https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXht1KgsbnF&md5=dc269026d21f0e114c25b120b3c1e9b9Mechanistic insights into glycosidase chemistryVocadlo, David J.; Davies, Gideon J.Current Opinion in Chemical Biology (2008), 12 (5), 539-555CODEN: COCBF4; ISSN:1367-5931. (Elsevier B.V.)A review. The enzymic hydrolysis of the glycosidic bond continues to gain importance, reflecting the critically important roles complex glycans play in health and disease as well as the rekindled interest in enzymic biomass conversion. Recent advances include the broadening of our understanding of enzyme reaction coordinates, through both computational and structural studies, improved understanding of enzyme inhibition through transition state mimicry and fascinating insights into mechanism yielded by phys. org. chem. approaches.
- 9(a) Yu, S.; Oh, J.; Li, F.; Kwon, Y.; Cho, H.; Shin, J.; Lee, S. K.; Kim, S. New scaffold for angiogenesis inhibitors discovered by targeted chemical transformations of wondonin natural products. ACS Med. Chem. Lett. 2017, 8, 1066– 1071, DOI: 10.1021/acsmedchemlett.7b00281[ACS Full Text.], [CAS], Google Scholar9ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsVOrsb%252FF&md5=7ae303dfa823b91a4cb37b07a8968b65New Scaffold for Angiogenesis Inhibitors Discovered by Targeted Chemical Transformations of Wondonin Natural ProductsYu, Shuai; Oh, Jedo; Li, Feng; Kwon, Yongseok; Cho, Hyunkyung; Shin, Jongheon; Lee, Sang Kook; Kim, SangheeACS Medicinal Chemistry Letters (2017), 8 (10), 1066-1071CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)The structure of wondonin marine natural products was renovated to attain new drug-like scaffolds. Wondonins have novel antiangiogenic properties without overt cytotoxicity. However, the chem. instability and synthetic complexity of wondonins have hindered their development as a new type of antiangiogenesis agent. Using a structure-based bioisosterism, the benzodioxole moiety was changed to benzothiazole, and the imidazole moiety was replaced by 1,2,3-triazole. The authors' efforts resulted in a new scaffold with enhanced antiangiogenic activity and minimized cytotoxicity. One compd. with this scaffold effectively inhibited hyaloid vessel formation in diabetic retinopathy mimic zebrafish model. The biol. findings together suggested the potential of the scaffold as a lead structure for development of antiangiogenic drugs with novel functions and as a probe to elucidate new biol. mechanisms assocd. with angiogenesis.(b) Huang, Z.; Williams, R. B.; Martin, S. M.; Lawrence, J. A.; Norman, V. L.; O’Neil-Johnson, M.; Harding, J.; Mangette, J. E.; Liu, S.; Guzzo, P. R.; Starks, C. M.; Eldridge, G. R. Bifidenone: structure-activity relationship and advanced preclinical candidate. J. Med. Chem. 2018, 61, 6736– 6747, DOI: 10.1021/acs.jmedchem.7b01644[ACS Full Text.], [CAS], Google Scholar9bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtlSmurrL&md5=92c58d29301a57d2567bf6a7918800f8Bifidenone: Structure-Activity Relationship and Advanced Preclinical CandidateHuang, Zhongping; Williams, Russell B.; Martin, Steven M.; Lawrence, Julie A.; Norman, Vanessa L.; ONeil-Johnson, Mark; Harding, Jim; Mangette, John E.; Liu, Shuang; Guzzo, Peter R.; Starks, Courtney M.; Eldridge, Gary R.Journal of Medicinal Chemistry (2018), 61 (15), 6736-6747CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Bifidenone is a novel natural tubulin polymn. inhibitor that exhibits antiproliferative activity against a range of human cancer cell lines, making it an attractive candidate for development. A synthetic route was previously developed to alleviate supply constraints arising from its isolation in microgram quantities from a Gabonese tree. Using that previously published route, the authors present here 42 analogs that were synthesized to examine the structure-activity relationship of bifidenone derivs. In addn. to in vitro cytotoxicity data, data from murine xenograft and pharmacokinetic studies were used to evaluate the analogs. Compds. 45b ((6S,7aR)-6-allyl-7a-[(R)-1-(2,5-difluoro-4-methoxyphenyl)propan-2-yl]-7,7a-dihydrobenzo[d][1,3]dioxol-5(6H)-one) and 46b ((6S,7aR)-6-allyl-7a-[(R)-1-(2-fluoro-5-hydroxy-4-methoxyphenyl)propan-2-yl]-7,7a-dihydrobenzo[d][1,3]dioxol-5(6H)-one) were found to demonstrate promising efficacy in murine xenograft expts., and 46b had significantly more potent in vitro antiproliferative activity against taxane-resistant cell lines compared to that of paclitaxel.(c) Corey, E. J.; Wu, Y-. J. Total synthesis of (±)-paeoniflorigenin and paeoniflorin. J. Am. Chem. Soc. 1993, 115, 8871– 8872, DOI: 10.1021/ja00072a063[ACS Full Text.], [CAS], Google Scholar9chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXjtFSntQ%253D%253D&md5=a8087825354cbe383f00d325c7eab2efTotal synthesis of (±)-paeoniflorigenin and paeoniflorinCorey, E. J.; Wu, Yong JinJournal of the American Chemical Society (1993), 115 (19), 8871-2CODEN: JACSAT; ISSN:0002-7863.The first total synthesis of (±)-paeniflorigenin the aglycon of paeoniflorin (I) and I itself has been accomplished.(d) Aicher, T. D.; Buszek, K. R.; Fang, F. G.; Forsyth, C. J.; Jung, S. H.; Kishi, Y.; Matelich, M. C.; Scola, P. M.; Spero, D. M.; Yoon, S. K. Total synthesis of halichondrin B and norhalichondrin B. J. Am. Chem. Soc. 1992, 114, 3162– 3164, DOI: 10.1021/ja00034a086[ACS Full Text.], [CAS], Google Scholar9dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK38XitlGgs7k%253D&md5=46522121b99caecee139b497c2a5e352Total synthesis of halichondrin B and norhalichondrin BAicher, Thomas D.; Buszek, Keith R.; Fang, Francis G.; Forsyth, Craig J.; Jung, Sun Ho; Kishi, Yoshito; Matelich, Michael C.; Scola, Paul M.; Spero, Denice M.; Yoon, Suk KyoonJournal of the American Chemical Society (1992), 114 (8), 3162-4CODEN: JACSAT; ISSN:0002-7863.The first total syntheses of the title compds.(I and II resp.) have been accomplished. These syntheses have established unambiguously the relative and abs. stereochemistry of I and II.(e) Fattorusso, C.; Persico, M.; Calcinai, B.; Cerrano, C.; Parapini, S.; Taramelli, D.; Novellino, E.; Romano, A.; Scala, F.; Fattorusso, E.; Taglialatela-Scafati, O. Manadoperoxides A-D from the Indonesian sponge Plakortis cfr. simplex. Further insights on the structure-activity relationships of simple 1,2-dioxane antimalarials. J. Nat. Prod. 2010, 73, 1138– 1145, DOI: 10.1021/np100196b[ACS Full Text.], [CAS], Google Scholar9ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXmvFaksL0%253D&md5=08a19ee02ba140011edab787728d0505Manadoperoxides A-D from the Indonesian Sponge Plakortis cfr. simplex. Further Insights on the Structure-Activity Relationships of Simple 1,2-Dioxane AntimalarialsFattorusso, Caterina; Persico, Marco; Calcinai, Barbara; Cerrano, Carlo; Parapini, Silvia; Taramelli, Donatella; Novellino, Ettore; Romano, Adriana; Scala, Fernando; Fattorusso, Ernesto; Taglialatela-Scafati, OrazioJournal of Natural Products (2010), 73 (6), 1138-1145CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)The new endoperoxyketal polyketides manadoperoxides A-D (I-IV) were isolated from the Indonesian sponge Plakortis cfr. simplex and their stereostructures established by means of spectroscopic data and semisynthetic transformations. Manadoperoxides were assayed in vitro against D10 and W2 strains of Plasmodium falciparum and showed moderate antimalarial activity compared to that of plakortin and peroxyplakoric B3 ester, the latter differing from manadoperoxide B only by minor structural details. This unexpected difference in the antimalarial activity has been rationalized on the basis of our recently published model for the interaction of 1,2-dioxanes with heme and prodn. of C-centered radicals toxic to the parasite. For the manadoperoxides, either the endoperoxide linkage is inaccessible to the heme iron or the O1 radical cannot evolve to produce a C-centered radical.(f) Chevallier, O. P.; Graham, S. F.; Alonso, E.; Duffy, C.; Silke, J.; Campbell, K.; Botana, L. M.; Elliott, C. T. New insights into the causes of human illness due to consumption of azaspiracid contaminated shellfish. Sci. Rep. 2015, 5, 9818, DOI: 10.1038/srep09818[Crossref], [PubMed], [CAS], Google Scholar.9fhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFOjtbjE&md5=464529d1244b8fa52e82cc9c3f69ad8fNew insights into the causes of human illness due to consumption of azaspiracid contaminated shellfishChevallier, O. P.; Graham, S. F.; Alonso, E.; Duffy, C.; Silke, J.; Campbell, K.; Botana, L. M.; Elliott, C. T.Scientific Reports (2015), 5 (), 9818CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)Azaspiracid (AZA) poisoning was unknown until 1995 when shellfish harvested in Ireland caused illness manifesting by vomiting and diarrhoea. Further in vivo/vitro studies showed neurotoxicity linked with AZA exposure. However, the biol. target of the toxin which will help explain such potent neurol. activity is still unknown. A region of Irish coastline was selected and shellfish were sampled and tested for AZA using mass spectrometry. An outbreak was identified in 2010 and samples collected before and after the contamination episode were compared for their metabolite profile using high resoln. mass spectrometry. Twenty eight ions were identified at higher concn. in the contaminated samples. Stringent bioinformatic anal. revealed putative identifications for seven compds. including, glutarylcarnitine, a glutaric acid metabolite. Glutaric acid, the parent compd. linked with human neurol. manifestations was subjected to toxicol. investigations but was found to have no specific effect on the sodium channel (as was the case with AZA). However in combination, glutaric acid (1mM) and azaspiracid (50nM) inhibited the activity of the sodium channel by over 50%. Glutaric acid was subsequently detected in all shellfish employed in the study. For the first time a viable mechanism for how AZA manifests itself as a toxin is presented.(g) Allan, K.; Stoltz, B. M. A concise total synthesis of (−)-quinocarcin via aryne annulation. J. Am. Chem. Soc. 2008, 130, 17270– 17271, DOI: 10.1021/ja808112y[ACS Full Text.], [CAS], Google Scholar9ghttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsVyhs7%252FM&md5=e8c16616481b4a7be5e46d8f45d11b2aA Concise Total Synthesis of (-)-Quinocarcin via Aryne AnnulationAllan, Kevin M.; Stoltz, Brian M.Journal of the American Chemical Society (2008), 130 (51), 17270-17271CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)A rapid asym. total synthesis of the tetrahydroisoquinoline antitumor antibiotic (-)-quinocarcin (I) was described. The sequence employed a mild fluoride-induced aryne annulation to build a key isoquinoline-contg. intermediate comprising the entire carbon scaffold of the natural product. This intermediate was advanced through six addnl. steps to the target alkaloid, providing the shortest synthetic route to (-)-quinocarcin reported to date.(h) Feng, X.; Bello, D.; Lowe, P. T.; Clark, J.; O’Hagan, D. Two 30-O-β-glucosylated nucleoside fluorometabolites related to nucleocidin in Streptomyces calvus. Chem. Sci. 2019, 10, 9501– 9505, DOI: 10.1039/C9SC03374B[Crossref], [PubMed], [CAS], Google Scholar.9hhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhs1Sgtb3M&md5=5f1728a9b710facb6b5dd7435f2c709dTwo 3'-O-β-glucosylated nucleoside fluorometabolites related to nucleocidin in Streptomyces calvusFeng, Xuan; Bello, Davide; Lowe, Phillip T.; Clark, Joshua; O'Hagan, DavidChemical Science (2019), 10 (41), 9501-9505CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)The antibiotic nucleocidin is a product of the soil bacterium Streptomyces calvus T-3018. It is among the very rare fluorine contg. natural products but is distinct from the other fluorometabolites in that it is not biosynthesised from 5'-fluorodeoxyadenosine via the fluorinase. It seems to have a unique enzymic fluorination process. We disclose here the structures of two 4'-fluoro-3'-O-β-glucosylated metabolites (F-Mets I and II) which appear and then disappear before nucleocidin prodn. in batch cultures of S. calvus. Full genome sequencing of S. calvus T-3018 and an anal. of the putative biosynthetic gene cluster for nucleocidin identified UDP-glucose dependent glucosyl transferase (nucGT) and glucosidase (nucGS) genes within the cluster. We demonstrate that these genes express enzymes that have the capacity to attach and remove glucose from the 3'-O-position of adenosine analogs. In the case of F-Met II, deglucosylation with the NucGS glucosidase generates nucleocidin suggesting a role in its biosynthesis. Gene knockouts of nucGT abolished nucelocidin prodn.(i) Whitley, R.; Alford, C.; Hess, F.; Buchanan, R. Vidarabine: a preliminary review of its pharmacological properties and therapeutic use. Drugs 1980, 20, 267– 282, DOI: 10.2165/00003495-198020040-00002[Crossref], [PubMed], [CAS], Google Scholar.9ihttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL3M%252FitlOmtA%253D%253D&md5=8e68ff27c0178f950bf13dc88df3ae5eVidarabine: a preliminary review of its pharmacological properties and therapeutic useWhitley R; Alford C; Hess F; Buchanan RDrugs (1980), 20 (4), 267-82 ISSN:0012-6667.Vidarabine is the first drug to become generally available in the USA for parenteral treatment of life-threatening or debilitating herpes simplex virus infections of man. For the past decade laboratory and clinical studies have been in progress to assess the pharmacology of the compound, its mechanism of action and its potential usefulness in clinical investigations. Currently, clinical usefulness has been established for herpes simplex infections of the eye and brain. Further studies in progress are evaluating the drug's ability to prevent progressive disease from herpes zoster in the immunocompromised patient, reduce mortality and morbidity from neonatal herpes simplex virus infection and improve outcome of chronic hepatitis B infection.(j) Mazumder, A.; Dwivedi, A.; du Plessis, J. Sinigrin and its therapeutic benefits. Molecules 2016, 21, 416, DOI: 10.3390/molecules21040416[Crossref], [PubMed], [CAS], Google Scholar.9jhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhs12rsLbI&md5=4503bd384eab808d509add5a8b1b9370Sinigrin and its therapeutic benefitsMazumder, Anisha; Dwivedi, Anupma; du Plessis, JeanettaMolecules (2016), 21 (4), 416/1-416/11CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)Sinigrin (allyl-glucosinolate or 2-propenyl-glucosinolate) is a natural aliph. glucosinolate present in plants of the Brassicaceae family, such as broccoli and brussels sprouts, and the seeds of Brassica nigra (mustard seeds) which contain high amts. of sinigrin. Since ancient times, mustard has been used by mankind for its culinary, as well as medicinal, properties. It has been systematically described and evaluated in the classical Ayurvedic texts. Studies conducted on the pharmacol. activities of sinigrin have revealed anti-cancer, antibacterial, antifungal, antioxidant, anti-inflammatory, wound healing properties and biofumigation. This current review will bring concise information about the known therapeutic activities of sinigrin. However, the information on known biol. activities is very limited and, hence, further studies still need to be conducted and its mol. mechanisms also need to be explored. This review on the therapeutic benefits of sinigrin can summarize current knowledge about this unique phytocompounds.(k) Kim, C. S.; Oh, J.; Subedi, L.; Kim, S. Y.; Choi, S. U.; Lee, K. R. Rare thioglycosides from the roots of Wasabia japonica. J. Nat. Prod. 2018, 81, 2129– 2133, DOI: 10.1021/acs.jnatprod.8b00570[ACS Full Text.], [CAS], Google Scholar9khttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhslCiurbL&md5=af67dd71f1af4fb9636267be93747ca1Rare Thioglycosides from the Roots of Wasabia japonicaKim, Chung Sub; Oh, Joonseok; Subedi, Lalita; Kim, Sun Yeou; Choi, Sang Un; Lee, Kang RoJournal of Natural Products (2018), 81 (9), 2129-2133CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)Six new thioglycosides (1-6) were characterized from the roots of W. japonica along with a known analog (7). Of these compds., 1-3 possessed a disulfide bridge connecting the carbohydrate motif and the aglycon, which is extremely rare in Nature. In particular, compd. 1 formed an unusual 1,4,5-oxadithiocane ring system. The structures of the isolated compds. were detd. through conventional NMR and HRMS data anal. procedure, and computational methods with advanced statistics were used for the configurational assignments of 1 and two pairs of inseparable epimers, 2/3 and 4/5. All compds. were evaluated for their anti-inflammatory, neuroprotective, and cytotoxic activities, with 1 showing weak anti-inflammatory activity (IC50 = 41.2 μM).(l) Igarashi, Y.; Asano, D.; Sawamura, M.; In, Y.; Ishida, T.; Imoto, M. Ulbactins F and G, polycyclic thiazoline derivatives with tumor cell migration inhibitory activity from Brevibacillus sp. Org. Lett. 2016, 18, 1658– 1661, DOI: 10.1021/acs.orglett.6b00531[ACS Full Text.], [CAS], Google Scholar9lhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XksV2msro%253D&md5=0f15e5e489c568fd1ff9ec389a655473Ulbactins F and G, polycyclic thiazoline derivatives with tumor cell migration inhibitory activity from Brevibacillus sp.Igarashi, Yasuhiro; Asano, Daisuke; Sawamura, Masashi; In, Yasuko; Ishida, Toshimasa; Imoto, MasayaOrganic Letters (2016), 18 (7), 1658-1661CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)Two new structurally unique compds. bearing a nitrogen- and sulfur-contg. tricyclic ring system, ulbactin F (I) and its diastereomeric isomer ulbactin G (II), were isolated from the culture ext. of a sponge-derived Brevibacillus sp. The structures and abs. configurations of I and II were detd. by NMR anal. and X-ray crystallog. anal. These compds. inhibit the migration of tumor cells in the submicromolar to micromolar range.(m) Iwasa, E.; Hamashima, Y.; Fujishiro, S.; Higuchi, E.; Ito, A.; Yoshida, M.; Sodeoka, M. Total synthesis of (+)-chaetocin and its analogues: their histone methyltransferase G9a inhibitory activity. J. Am. Chem. Soc. 2010, 132, 4078– 4079, DOI: 10.1021/ja101280p[ACS Full Text.], [CAS], Google Scholar9mhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXivVOgtbg%253D&md5=cae6c5ac86d28076e8b8988f8932e7acTotal Synthesis of (+)-Chaetocin and its Analogues: Their Histone Methyltransferase G9a Inhibitory ActivityIwasa, Eriko; Hamashima, Yoshitaka; Fujishiro, Shinya; Higuchi, Eisuke; Ito, Akihiro; Yoshida, Minoru; Sodeoka, MikikoJournal of the American Chemical Society (2010), 132 (12), 4078-4079CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)The first total synthesis of (+)-chaetocin (I) has been accomplished in nine steps starting from known N-Cbz-N-Me-serine using radical α-bromination reaction and Co(I)-mediated reductive dimerization reaction as key reactions. The enantiomers show comparable inhibitory activity toward histone methyltransferase (HMT) G9a, but analogs without the sulfur functionality are inactive.(n) Zipperer, A.; Konnerth, M.; Laux, C.; Berscheid, A.; Janek, D.; Weidenmaier, C.; Burian, M.; Schilling, N. A.; Slavetinsky, C.; Marschal, M.; Willmann, M.; Kalbacher, H.; Schittek, B.; Brötz-Oesterhelt, H.; Grond, S.; Peschel, A.; Krismer, B. Human commensals producing a novel antibiotic impair pathogen colonization. Nature 2016, 535, 511– 516, DOI: 10.1038/nature18634[Crossref], [PubMed], [CAS], Google Scholar.9nhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xht1Ont73P&md5=04c4e8b4dac5aa1c56edf164e8360a3dHuman commensals producing a novel antibiotic impair pathogen colonizationZipperer, Alexander; Konnerth, Martin C.; Laux, Claudia; Berscheid, Anne; Janek, Daniela; Weidenmaier, Christopher; Burian, Marc; Schilling, Nadine A.; Slavetinsky, Christoph; Marschal, Matthias; Willmann, Matthias; Kalbacher, Hubert; Schittek, Birgit; Broetz-Oesterhelt, Heike; Grond, Stephanie; Peschel, Andreas; Krismer, BernhardNature (London, United Kingdom) (2016), 535 (7613), 511-516CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)Nasal Staphylococcus lugdunensis strains produce lugdunin, a novel thiazolidine-contg. cyclic peptide antibiotic that prohibits colonization by Staphylococcus aureus, and a rare example of a non-ribosomally synthesized bioactive compd. from human-assocd. bacteria. Lugdunin is bactericidal against major pathogens, effective in animal models, and not prone to causing development of resistance in S. aureus. Notably, human nasal colonization by S. lugdunensis was assocd. with a significantly reduced S. aureus carriage rate, suggesting that lugdunin or lugdunin-producing commensal bacteria could be valuable for preventing staphylococcal infections. Moreover, human microbiota should be considered as a source for new antibiotics.(o) Foo, K.; Newhouse, T.; Mori, I.; Takayama, H.; Baran, P. S. Total synthesis guided structure elucidation of (+)-psychotetramine. Angew. Chem., Int. Ed. 2011, 50, 2716– 2719, DOI: 10.1002/anie.201008048[Crossref], [CAS], Google Scholar.9ohttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXivVGhtbc%253D&md5=9f6c0fa7f5dea05af6706a4c424613cdTotal Synthesis Guided Structure Elucidation of (+)-PsychotetramineFoo, Klement; Newhouse, Timothy; Mori, Ikue; Takayama, Hiromitsu; Baran, Phil S.Angewandte Chemie, International Edition (2011), 50 (12), 2716-2719, S2716/1-S2716/61CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)The title compd. I was prepd. and its structure was solved. The pursuit of this complex natural product also led to an efficient enantioselective synthesis of the related alkaloid (+)-psychotrimine II, an improved procedure for direct-indole aniline coupling, and one of the most complex and demanding contexts for a Buchwald-Hartwig amination.(p) Ohyabu, N.; Nishikawa, T.; Isobe, M. First asymmetric total synthesis of tetrodotoxin. J. Am. Chem. Soc. 2003, 125, 8798– 8805, DOI: 10.1021/ja0342998[ACS Full Text], [CAS], Google Scholar9phttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXkvFWlsr4%253D&md5=cd58508c4ad88a86568810133281fe64First Asymmetric Total Synthesis of TetrodotoxinOhyabu, Norio; Nishikawa, Toshio; Isobe, MinoruJournal of the American Chemical Society (2003), 125 (29), 8798-8805CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Tetrodotoxin, a toxic principle of puffer fish poisoning, is one of the most famous marine natural products because of the complex structure having many functional groups and its potent biol. activity leading to death. Since the structure elucidation in 1964, this toxin has been recognized as a formidable target mol. for total synthesis. We have recently achieved the first asym. total synthesis from 2-acetoxy-tri-O-acetyl-D-glucal as a chiral starting material. The highly hydroxylated cyclohexane ring was constructed by Claisen rearrangement and regioselective hydroxylations of an acetone moiety and an intramol. directed aldol condensation of the precursor having Me ketone with dihydroxyacetone, which was synthesized through Sonogashira coupling. Installation of nitrogen functionality was unsuccessful through an attempted Overman rearrangement. We, therefore, employed a new intramol. conjugate addn. strategy between the carbamate and unsatd. ester groups. The α-hydroxyl lactone moiety was synthesized through an intramol. epoxide opening by the Z-enolate of aldehyde, which was followed by oxidn.-redn. of the resulting cyclic vinyl ether. The lactone was then converted to a protected ortho ester, and then gunanidinylation was followed by cleavage of the 1,2-glycol to give the fully protected tetrodotoxin. Selection of the protective groups has finally led us to accomplish the total synthesis of tetrodotoxin in an enantiomerically pure form. All the stereogenic centers were controlled with high selectivity, and the hydroxyl groups were differently protected to discriminate for the future analog synthesis of a bioorg. program. The synthetic tetrodotoxin was purified by ion exchange chromatog. and characterized to be identical with the natural compd.
- 10(a) Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell, N. A. Applications of fluorine in medicinal chemistry. J. Med. Chem. 2015, 58, 8315– 8359, DOI: 10.1021/acs.jmedchem.5b00258[ACS Full Text.], [CAS], Google Scholar10ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1ajs7%252FK&md5=9995829a94a8c0b8d9fb0d21bdfd5a1dApplications of Fluorine in Medicinal ChemistryGillis, Eric P.; Eastman, Kyle J.; Hill, Matthew D.; Donnelly, David J.; Meanwell, Nicholas A.Journal of Medicinal Chemistry (2015), 58 (21), 8315-8359CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review with meta-anal. The role of fluorine in drug design and development is expanding rapidly as we learn more about the unique properties assocd. with this unusual element and how to deploy it with greater sophistication. The judicious introduction of fluorine into a mol. can productively influence conformation, pKa, intrinsic potency, membrane permeability, metabolic pathways, and pharmacokinetic properties. In addn., 18F has been established as a useful positron emitting isotope for use with in vivo imaging technol. that potentially has extensive application in drug discovery and development, often limited only by convenient synthetic accessibility to labeled compds. The wide ranging applications of fluorine in drug design are providing a strong stimulus for the development of new synthetic methodologies that allow more facile access to a wide range of fluorinated compds. In this review, we provide an update on the effects of the strategic incorporation of fluorine in drug mols. and applications in positron emission tomog.(b) Meanwell, N. A. Fluorine and fluorinated motifs in the design and application of bioisosteres for drug design. J. Med. Chem. 2018, 61, 5822– 5880, DOI: 10.1021/acs.jmedchem.7b01788[ACS Full Text.], [CAS], Google Scholar10bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitV2qu7w%253D&md5=2d0ce3326c7ff932da8d7d26972ced14Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug DesignMeanwell, Nicholas A.Journal of Medicinal Chemistry (2018), 61 (14), 5822-5880CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The electronic properties and relatively small size of fluorine endow it with considerable versatility as a bioisostere and it has found application as a substitute for lone pairs of electrons, the hydrogen atom, and the Me group while also acting as a functional mimetic of the carbonyl, carbinol, andnitrile moieties. In this context, fluorine substitution can influence the potency, conformation, metab., membrane permeability, and P-gp recognition of a mol. and temper inhibition of the hERG channel by basic amines. However, as a consequence of the unique properties of fluorine, it features prominently in the design of higher order structural metaphors that are more esoteric in their conception and which reflect a more sophisticated mol. construction that broadens biol. mimesis. In this Perspective, applications of fluorine in the construction of bioisosteric elements designed to enhance the in vitro and in vivo properties of a mol. are summarized.(c) Liu, B.; Thayumanavan, S. Substituent effects on the pH sensitivity of acetals and ketals and their correlation with encapsulation stability in polymeric nanogels. J. Am. Chem. Soc. 2017, 139, 2306– 2317, DOI: 10.1021/jacs.6b11181[ACS Full Text], [CAS], Google Scholar10chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsVagt78%253D&md5=b265a1435bcc42b4fce000034d13d279Substituent Effects on the pH Sensitivity of Acetals and Ketals and Their Correlation with Encapsulation Stability in Polymeric NanogelsLiu, Bin; Thayumanavan, S.Journal of the American Chemical Society (2017), 139 (6), 2306-2317CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)The effect of structural variations in acetal- and ketal-based linkers upon their degrdn. kinetics is studied through the design, synthesis, and study of six series of mols., comprising a total of 18 different mols. Through this systematic study, the structural fine-tuning of the linkers allows access to variations in kinetics of degrdn. of >6 orders of magnitude. Hammett correlations show that the ρ value for the hydrolysis of benzylidene acetals is ∼-4.06, which is comparable to an SN1-like process. There is a strong, developing pos. charge at the benzylic position in the transition state during the degrdn. of acetals. This pos. charged transition state is consistent with the relative degrdn. rates of acetals vs. ketals (correlated to stabilities of 1°, 2°, and 3° carboxonium ion type intermediates) and the obsd. effect of proximal electron-withdrawing groups upon the degrdn. rates. Following this, the authors studied whether the degrdn. kinetics study correlates with pH-sensitive variations in the host-guest characteristics of polymeric nanogels that contains these acetal or ketal moieties as crosslinking functionalities. Indeed, the trends obsd. in the small mol. degrdn. have clear correlations with the encapsulation stability of guest mols. within these polymeric nanogels. The implications of this fundamental study extend to a broad range of applications, well beyond the polymeric nanogel examples studied here.
- 11(a) Gillies, E. R.; Goodwin, A. P.; Fréchet, J. M. Acetals as pH-sensitive linkages for drug delivery. Bioconjugate Chem. 2004, 15, 1254– 1263, DOI: 10.1021/bc049853x[ACS Full Text.], [CAS], Google Scholar11ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXotlartbY%253D&md5=e9a5cb11f2b4130753c53742b8ed1783Acetals as pH-sensitive linkages for drug deliveryGillies, Elizabeth R.; Goodwin, Andrew P.; Frechet, Jean M. J.Bioconjugate Chemistry (2004), 15 (6), 1254-1263CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)PH-sensitive linkages designed to undergo hydrolysis at mildly acidic pH can trigger the release of therapeutics selectively at targets such as tumor and inflammatory tissues and in the endosomes and lysosomes of cells. Acetals have the potential to be used as linkages for a range of alc. functionalities, and, by altering their chem. structure, it is possible to tune their hydrolysis rate. The synthesis of four conjugates of model drug mols. with PEO using acetals of varying chem. structure were described herein. Primary and secondary alcs., as well as syn-1,2-diols, were incorporated in the conjugates. The hydrolysis kinetics were investigated by HPLC, and the conjugates had half-lives ranging from less than 1 min to several days at pH 5.0, with slower hydrolysis at pH 7.4 in all cases. These acetal linkages were therefore promising for use in a variety of drug delivery applications ranging from polymer-drug conjugates to pH-sensitive micelles and nanoparticulate systems.(b) Gillies, E. R.; Fréchet, J. M. pH-Responsive copolymer assemblies for controlled release of doxorubicin. Bioconjugate Chem. 2005, 16, 361– 368, DOI: 10.1021/bc049851c[ACS Full Text.], [CAS], Google Scholar11bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtF2jsL8%253D&md5=fd200f7d1acbf478e52e2ad5179e1673pH-responsive copolymer assemblies for controlled release of doxorubicinGillies, Elizabeth R.; Frechet, Jean M. J.Bioconjugate Chemistry (2005), 16 (2), 361-368CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)PH-Responsive drug carriers have the potential to provide selective drug release at therapeutic targets including tumors and in acidic intracellular vesicles such as endosomes and lysosomes. We have developed a new approach to the design of acid-sensitive micelles by incorporating hydrophobic acetal groups on the core block of a micelle-forming block copolymer. Hydrolysis of the acetals at mildly acidic pH is designed to reveal polar groups on the core-forming block, thus changing its soly. and disrupting the micelle, triggering drug release. The anticancer drug doxorubicin (DOX) was encapsulated in these pH-sensitive micelles, and the acetal hydrolysis rates and DOX release rates were detd. in the pH range of 4.0 to 7.4 and were compared to those of control systems. The micelle disruption was investigated by dynamic light scattering. The in vitro toxicities of the empty and DOX-loaded micelles were detd., and the intracellular fate of the encapsulated DOX was compared to free DOX using fluorescence confocal microscopy.(c) Huang, F.; Cheng, R.; Meng, F.; Deng, C.; Zhong, Z. Micelles based on acid degradable poly(acetal urethane): preparation, pH-sensitivity, and triggered intracellular drug release. Biomacromolecules 2015, 16, 2228– 2236, DOI: 10.1021/acs.biomac.5b00625[ACS Full Text.], [CAS], Google Scholar11chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVOit73O&md5=b8de89a45212089b9bf33aea95f20aa5Micelles Based on Acid Degradable Poly(acetal urethane): Preparation, pH-Sensitivity, and Triggered Intracellular Drug ReleaseHuang, Fushi; Cheng, Ru; Meng, Fenghua; Deng, Chao; Zhong, ZhiyuanBiomacromolecules (2015), 16 (7), 2228-2236CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)Polyurethanes are a unique class of biomaterials that are widely used in medical devices. In spite of their easy synthesis and excellent biocompatibility, polyurethanes are less explored for controlled drug delivery due to their slow or lack of degrdn. In this paper, we report the design and development of novel acid degradable poly(acetal urethane) (PAU) and corresponding triblock copolymer micelles for pH-triggered intracellular delivery of a model lipophilic anticancer drug, doxorubicin (DOX). PAU with Mn ranging from 4.3 to 12.3 kg/mol was conveniently prepd. from polycondensation reaction of lysine diisocyanate (LDI) and a novel diacetal-contg. diol, terephthalilidene-bis(trimethylolethane) (TPABTME) using dibutyltin dilaurate (DBTDL) as a catalyst in N,N-dimethylformamide (DMF). The thiol-ene click reaction of Allyl-PAU-Allyl with thiolated PEG (Mn = 5.0 kg/mol) afforded PEG-PAU-PEG triblock copolymers that readily formed micelles with av. sizes of about 90-120 nm in water. The dynamic light scattering (DLS) measurements revealed fast swelling and disruption of micelles under acidic pH. UV/vis spectroscopy corroborated that acetal degrdn. was accelerated at pH 4.0 and 5.0. The in vitro release studies showed that doxorubicin (DOX) was released in a controlled and pH-dependent manner, in which ca. 96%, 73%, and 30% of drug was released within 48 h at pH 4.0, 5.0, and 7.4, resp. Notably, MTT assays displayed that DOX-loaded PEG-PAU-PEG micelles had a high in vitro antitumor activity in both RAW 264.7 and drug-resistant MCF-7/ADR cells. The confocal microscopy and flow cytometry expts. demonstrated that PEG-PAU-PEG micelles mediated efficient cytoplasmic delivery of DOX. Importantly, blank PEG-PAU-PEG micelles were shown to be nontoxic to RAW 264.7 and MCF-7/ADR cells even at a high concn. of 1.5 mg/mL. Hence, micelles based on poly(acetal urethane) have appeared as a new class of biocompatible and acid-degradable nanocarriers for efficient intracellular drug delivery.(d) Cui, L.; Cohen, J. L.; Chu, C. K.; Wich, P. R.; Kierstead, P. H.; Fréchet, J. M. Conjugation chemistry through acetals toward a dextran-based delivery system for controlled release of siRNA. J. Am. Chem. Soc. 2012, 134, 15840– 15848, DOI: 10.1021/ja305552u[ACS Full Text.], [CAS], Google Scholar11dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhtlaisr3L&md5=e5ba3b8bec76608e7dbb823bf3cd501bConjugation Chemistry through Acetals toward a Dextran-Based Delivery System for Controlled Release of siRNACui, Lina; Cohen, Jessica L.; Chu, Crystal K.; Wich, Peter R.; Kierstead, Paul H.; Frechet, Jean M. J.Journal of the American Chemical Society (2012), 134 (38), 15840-15848CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)New conjugation chem. for polysaccharides, exemplified by dextran, was developed to enable the attachment of therapeutic or other functional moieties to the polysaccharide through cleavable acetal linkages. The acid-lability of the acetal groups allows the release of therapeutics under acidic conditions, such as that of the endocytic compartments of cells, regenerating the original free polysaccharide in the end. The phys. and chem. behavior of these acetal groups can be adjusted by modifying their stereoelectronic and steric properties, thereby providing materials with tunable degrdn. and release rates. We have applied this conjugation chem. in the development of water-sol. siRNA carriers, namely acetal-linked amino-dextrans, with various amine structures attached through either slow- or fast-degrading acetal linker. The carriers with the best combination of amine moieties and structural compn. of acetals showed high in vitro transfection efficiency and low cytotoxicity in the delivery of siRNA.(e) Hong, B. J.; Chipre, A. J.; Nguyen, S. T. Acid-degradable polymer-caged lipoplex (PCL) platform for siRNAdelivery: facile cellular triggered release of siRNA. J. Am. Chem. Soc. 2013, 135, 17655– 17658, DOI: 10.1021/ja404491r[ACS Full Text.], [CAS], Google Scholar11ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtlOktrjE&md5=b7e0f90d673e3bd911ecaa1735a34199Acid-Degradable Polymer-Caged Lipoplex (PCL) Platform for siRNA Delivery: Facile Cellular Triggered Release of siRNAHong, Bong Jin; Chipre, Anthony J.; Nguyen, SonBinh T.Journal of the American Chemical Society (2013), 135 (47), 17655-17658CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)An acid-degradable polymer-caged lipoplex (PCL) platform consisting of a cationic lipoplex core and a biocompatible, pH-responsive polymer shell has been developed for the effective delivery of small interfering RNA (siRNA) through a combination of facile loading, rapid acid-triggered release, cellular internalization, and effective endosomal escape. In vitro testing of this degradable PCL delivery platform reveals ∼45- and ∼2.5-fold enhancement of enhanced green fluorescent protein knockdown in cancer cells in comparison to either free siRNA or siRNA-loaded non-acid-degradable lipoplex formulations, resp.(f) Broaders, K. E.; Cohen, J. A.; Beaudette, T. T.; Bachelder, E. M.; Fréchet, J. M. Acetalated dextran is a chemically and biologically tunable material for particulate immunotherapy. Proc. Natl. Acad. Sci. U. S. A. 2009, 106, 5497– 5502, DOI: 10.1073/pnas.0901592106[Crossref], [PubMed], [CAS], Google Scholar.11fhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXkvFOnsrk%253D&md5=8d04187079deedd36810463a6a613b3cAcetylated dextran is a chemically and biologically tunable material for particulate immunotherapyBroaders, Kyle E.; Cohen, Joel A.; Beaudette, Tristan T.; Bachelder, Eric M.; Frechet, Jean M. J.Proceedings of the National Academy of Sciences of the United States of America (2009), 106 (14), 5497-5502CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Materials that combine facile synthesis, simple tuning of degrdn. rate, processability, and biocompatibility are in high demand for use in biomedical applications. The authors report on acetylated dextran, a biocompatible material that can be formed into microparticles with degrdn. rates that are tunable over 2 orders of magnitude depending on the degree and type of acetal modification. Varying the degrdn. rate produces particles that perform better than poly(lactic-co-glycolic acid) and iron oxide, two commonly studied materials used for particulate immunotherapy, in major histocompatibility complex class, I (MHC I) and MHC II presentation assays. Modulating the material properties leads to antigen presentation on MHC I via pathways that are dependent or independent of the transporter assocd. with antigen processing. To the best of the authors' knowledge, this is the only example of a material that can be tuned to operate on different immunol. pathways while maximizing immunol. presentation.(g) Lee, S.; Wang, W.; Lee, Y.; Sampson, N. S. Cyclic acetals as cleavable linkers for affinity capture. Org. Biomol. Chem. 2015, 13, 8445– 8452, DOI: 10.1039/C5OB01056J[Crossref], [PubMed], [CAS], Google Scholar11ghttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFWgurfF&md5=3d7c45da0e983ec1ab46612af5e85501Cyclic acetals as cleavable linkers for affinity captureLee, Siyeon; Wang, Wei; Lee, Younjoo; Sampson, Nicole S.Organic & Biomolecular Chemistry (2015), 13 (31), 8445-8452CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)Labeling proteins with biotin is a widely used method to identify target proteins due to biotin's strong binding affinity for streptavidin. Combined with alkyne-azide cycloaddn., which enables the coupling of probes to targeted proteins, biotin tags linked to an alkyne or azide have become a powerful tool for purifn. and anal. of proteins in proteomics. However, biotin requires harsh elution conditions to release the captured protein from the bead matrix. Use of these conditions reduces signal to noise and complicates the anal. To improve affinity capture, cleavable linkers have been introduced. Here, the authors demonstrate the use of a cyclic acetal biotin probe that was prepd. easily from com. available starting materials, is stable to cell lysates, yet is cleaved under mildly acidic conditions, and which provides an aldehyde for further elaboration of the protein, if desired.
- 12Maryanoff, B. E. Phenotypic assessment and the discovery of topiramate. ACS Med. Chem. Lett. 2016, 7, 662– 665, DOI: 10.1021/acsmedchemlett.6b00176[ACS Full Text], [CAS], Google Scholar12https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XpsF2mtLc%253D&md5=227d9ac65313ec8a3401393ba4715390Phenotypic Assessment and the Discovery of TopiramateMaryanoff, Bruce E.ACS Medicinal Chemistry Letters (2016), 7 (7), 662-665CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)The role of phenotypic assessment in drug discovery is discussed, along with the discovery and development of TOPAMAX (topiramate), a billion-dollar mol. for the treatment of epilepsy and migraine.
- 13Hale, J. L.; Mills, S. G.; MacCoss, M.; Finke, P. E.; Cascieri, M. A.; Sadowski, S.; Ber, E.; Chicchi, G. G.; Kurtz, M.; Metzger, J.; Eiermann, G.; Tsou, N. N.; Tattersall, F. D.; Rupniak, N. M.; Williams, A. R.; Rycroft, W.; Hargreaves, R.; MacIntyre, D. E. Structural optimization affording2-(R)-(1-(R)-3,5-bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-oxo-1,2,4-triazol-5-yl)methylmorpholine, a potent, orally active, long-acting morpholine acetal human NK-1 receptor antagonist. J. Med. Chem. 1998, 41, 4607– 4614, DOI: 10.1021/jm980299k[ACS Full Text], [CAS], Google Scholar13https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXmtlansrY%253D&md5=0ca98b5fb6a2957deffee22fa62aa988Structural Optimization Affording 2-(R)-(1-(R)-3,5-Bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4- (3-oxo-1,2,4-triazol-5-yl)methylmorpholine, a Potent, Orally Active, Long-Acting Morpholine Acetal Human NK-1 Receptor AntagonistHale, Jeffrey J.; Mills, Sander G.; MacCoss, Malcolm; Finke, Paul E.; Cascieri, Margaret A.; Sadowski, Sharon; Ber, Elzbieta; Chicchi, Gary G.; Kurtz, Marc; Metzger, Joseph; Eiermann, George; Tsou, Nancy N.; Tattersall, F. David; Rupniak, Nadia M. J.; Williams, Angela R.; Rycroft, Wayne; Hargreaves, Richard; MacIntyre, D. EuanJournal of Medicinal Chemistry (1998), 41 (23), 4607-4614CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Structural modifications requiring novel synthetic chem. were made to the morpholine acetal human neurokinin-1 (hNK-1) receptor antagonist L-742694, and this resulted in the discovery of 2-(R)-(1-(R)-3,5-bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-oxo-1,2,4-triazol-5-yl)methyl morpholine (I). This modified compd. is a potent, long-acting hNK-1 receptor antagonist as evidenced by its ability to displace [125I]Substance P from hNK-1 receptors stably expressed in CHO cells (IC50 = 0.09 ± 0.06 nM) and by the measurement of the rates of assocn. (k1 = 2.8 ± 1.1 × 108 M-1 min-1) and dissocn. (k-1 = 0.0054 ± 0.003 min-1) of I from hNK-1 expressed in Sf9 membranes which yields Kd = 19 ± 12 pM and a t1/2 for receptor occupancy equal to 154 ± 75 min. Inflammation in the guinea pig induced by a resiniferatoxin challenge (with NK-1 receptor activation mediating the subsequent increase in vascular permeability) is inhibited in a dose-dependent manner by the oral preadmininstration of I (IC50 (1 h) = 0.008 mg/kg; IC90 (24 h) = 1.8 mg/kg), indicating that this compd. has good oral bioavailability and peripheral duration of action. Central hNK-1 receptor stimulation is also inhibited by the systemic preadministration of I as shown by its ability to block an NK-1 agonist-induced foot tapping response in gerbils (IC50 (4 h) = 0.04 ± 0.006 mg/kg; IC50 (24 h) = 0.33 ± 0.017 mg/kg) and by its antiemetic actions in the ferret against cisplatin challenge. The activity of I at extended time points in these preclin. animal models sets it apart from earlier morpholine antagonists (such as L-742694), and the piperidine antagonists CP 122721 and GR 205171 and could prove to be an advantage in the treatment of chronic disorders related to the actions of Substance P. In part on the basis of these data, I has been identified as a potential clin. candidate for the treatment of peripheral pain, migraine, chemotherapy-induced emesis, and various psychiatric disorders.
- 14Delost, M. D.; Smith, D. T.; Anderson, B. J.; Njardarson, J. T. From oxiranes to oligomers: architectures of U.S. FDA approved pharmaceuticals containing oxygen heterocycles. J. Med. Chem. 2018, 61, 10996– 11020, DOI: 10.1021/acs.jmedchem.8b00876[ACS Full Text], [CAS], Google Scholar14https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtlGit7nE&md5=18f3979c80513bfbbc263dd5945c63f0From Oxiranes to Oligomers: Architectures of U.S. FDA Approved Pharmaceuticals Containing Oxygen HeterocyclesDelost, Michael D.; Smith, David T.; Anderson, Benton J.; Njardarson, Jon T.Journal of Medicinal Chemistry (2018), 61 (24), 10996-11020CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Oxygen heterocycles are the second most common type of heterocycles that appear as structural components of U.S. Food and Drug Administration (FDA) approved pharmaceuticals. Anal. of our database of drugs approved through 2017 reveals 311 distinct pharmaceuticals contg. at least one oxygen heterocycle. Most prevalent among these are pyranoses, with furanoses, macrolactones, morpholines, and dioxolanes rounding off the top five. The main body of this Perspective is organized according to ring size, commencing with three- and four-membered rings and ending with macrocycles, polymers, and unusual oxygen-contg. heterocycles. For each section, all oxygen heterocycle-contg. drugs are presented along with a brief discussion about structural and drug application patterns.
- 15(a) De Wolfe, R. H.; Ivanetich, K. M.; Perry, N. F. General acid catalysis in benzophenone ketal hydrolysis. J. Org. Chem. 1969, 34, 848– 854, DOI: 10.1021/jo01256a015[ACS Full Text.], [CAS], Google Scholar15ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF1MXktFahsL8%253D&md5=7fdcaddba53337826472b32f180e92b7General acid catalysis in benzophenone ketal hydrolysisDe Wolfe, Robert H.; Ivanetich, Kathryn M.; Perry, Noreen F.Journal of Organic Chemistry (1969), 34 (4), 848-54CODEN: JOCEAH; ISSN:0022-3263.Benzophenone diethyl ketal (I), 2,2-diphenyl-1,3-dioxolane, 2,2-bis(p-methoxyphenyl)-1,3-dioxolane, 2,2-di(p-tolyl)-1,3-dioxolane and 2,2-bis-(p-chlorophenyl)-1,3-dioxolane were prepd. and their kinetics of hydrolysis studied in aq. dioxane formate, chloroacetate, and dichloroacetate buffers. General acid catalysis was observed for hydrolysis of ketals of benzophenone, 4,4'-dimenthoxybenzo-phenone, and 4,4'-dimethylbenzophenone in chloroacetate and dichloroacetate buffers. Catalytic coeffs. for the buffer acids and for H+ were derived from the kinetic data. H+ catalytic coeffs. correlate closely with Hammett's substituent consts. for the para substituents. The entropy of activation for H+-catalyzed hydrolysis is near zero for I and slightly neg. for the 2,2-diaryl-1,3-dioxolanes. The relation between acetal and ketal structures and the mechanisms (A1 or SE2) by which they hydrolyze are discussed.(b) Fife, T. H. General acid catalysis of acetal, ketal, and ortho ester hydrolysis. Acc. Chem. Res. 1972, 5, 264– 272, DOI: 10.1021/ar50056a002[ACS Full Text.], [CAS], Google Scholar15bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE38XltVSgtrw%253D&md5=6e5093eaa131da89ec2413dc7ff8f096General acid catalysis of acetal, ketal, and ortho ester hydrolysisFife, Thomas H.Accounts of Chemical Research (1972), 5 (8), 264-72CODEN: ACHRE4; ISSN:0001-4842.The structural features in acetals and ketals that will give rise to general acid catalyzed hydrolysis reactions have been determined. General acid catalysis by buffer acids will be detectable if the leaving group is good (a phenol) and basicity is low in cases where a moderately stable carbonium ion is formed as an intermediate. General acid catalysis will result when the leaving group is poor (an aliphatic alcohol) if the carbonium ion intermediate is exceedingly stable (an alkoxytropylium ion) or if there is great steric strain in the ground state which is relieved in the transition state. Intramolecular general acid catalysis by a substituent carboxyl group is observed with acetals having good leaving groups and giving rise to relatively stable oxo-carbonium ions so that buffer acid catalysis can be detected in hydrolysis of the unsubstituted compounds. In these reactions the efficiency of intra to intermolecular catalysis is quite large, and rate enhancements of 105-109 take place in comparison with suitable derivatives in which carboxyl group participation is not possible. The mechanism of action of lysozyme is discussed from the standpoint of this information.(c) Cordes, E. H.; Bull, H. G. Mechanism and catalysis for hydrolysis of acetals, ketals, and ortho esters. Chem. Rev. 1974, 74, 581– 603, DOI: 10.1021/cr60291a004[ACS Full Text.], [CAS], Google Scholar15chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE2cXlsFWisL4%253D&md5=362eab6033de06eb30dd958a0c221a79Mechanism and catalysis for hydrolysis of acetals, ketals, and ortho estersCordes, E. H.; Bull, H. G.Chemical Reviews (Washington, DC, United States) (1974), 74 (5), 581-603CODEN: CHREAY; ISSN:0009-2665.A review with 99 refs.(d) Wasserman, H. H.; Clark, G. M.; Turley, P. C. Recent aspects of cyclopropanone chemistry. In: Stereochemistry I. Topics in Current Chemistry Fortschritte der Chemischen Forschung 1974, 47, 73– 156, DOI: 10.1007/3-540-06648-9_9[Crossref], [CAS], Google Scholar.15dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE2cXkvFWjur4%253D&md5=f79e09ef0a01614705031245c4cc70ceRecent aspects of cyclopropanone chemistryWasserman, Harry H.; Clark, George M.; Turley, Patricia C.Topics in Current Chemistry (1974), 47 (), 73-156CODEN: TPCCAQ; ISSN:0340-1022.A review with 140 refs.(e) Deslongchamps, P.; Dory, Y. L.; Li, S. The relative rate of hydrolysis of a series of acyclic and six-membered cyclic acetals, ketals, orthoesters, and orthocarbonates. Tetrahedron 2000, 56, 3533– 3537, DOI: 10.1016/S0040-4020(00)00270-2[Crossref], [CAS], Google Scholar.15ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXjvFOqtbg%253D&md5=e748b95ddb87192eea8b186ba929e239The relative rate of hydrolysis of a series of acyclic and six-membered cyclic acetals, ketals, orthoesters, and orthocarbonatesDeslongchamps, Pierre; Dory, Yves L.; Li, ShiguiTetrahedron (2000), 56 (22), 3533-3537CODEN: TETRAB; ISSN:0040-4020. (Elsevier Science Ltd.)The relative rate of hydrolysis of these compds. is rationalized by considering the influence of steric, inductive and stereo-electronic effects on the hydrolysis reaction mechanism.(f) Li, S.; Dory, Y. L.; Deslongchamps, P. On the relative rate of hydrolysis of a series of ketals and their proton affinities. Isr. J. Chem. 2000, 40, 209– 215, DOI: 10.1560/QRH5-Q3N0-0XA6-PT9Y[Crossref], [CAS], Google Scholar.15fhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXlsVCktrc%253D&md5=72f0c2ac31bf5bb5bd5706b97161ee49On the relative rate of hydrolysis of a series of ketals and their proton affinitiesLi, Shigui; Dory, Yves L.; Deslongchamps, PierreIsrael Journal of Chemistry (2000), 40 (3-4), 209-215CODEN: ISJCAT; ISSN:0021-2148. (Laser Pages Publishing)The relative rates of hydrolysis of cyclic and acyclic ketals were studied. Their reactivity toward acid hydrolysis is explained by considering the ease of protonation and the cleavage of the C-O bond. The exptl. work and the theor. calcns. of the proton affinities of the ketals suggest that the rate-limiting step of hydrolysis of ketals is a concerted protonation and cleavage of the C-O bond. The relative proton affinity is considered to be a direct consequence of the ease of proper lone pair orbital alignment on the O atoms of the various ketals.(g) Repetto, S. L.; Costello, J. F.; Butts, C. P.; Lam, J. K. W.; Ratcliffe, N. M. The hydrolysis of geminal ethers: a kinetic appraisal of orthoesters and ketals. Beilstein J. Org. Chem. 2016, 12, 1467– 1475, DOI: 10.3762/bjoc.12.143[Crossref], [PubMed], [CAS], Google Scholar.15ghttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslKjtbnP&md5=423ed1261e2ea6ebe3f8ddd4cdce2807The hydrolysis of geminal ethers: a kinetic appraisal of orthoesters and ketalsRepetto, Sonia L.; Costello, James F.; Butts, Craig P.; Lam, Joseph K. W.; Ratcliffe, Norman M.Beilstein Journal of Organic Chemistry (2016), 12 (), 1467-1475CODEN: BJOCBH; ISSN:1860-5397. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)A novel approach to protecting jet fuel against the effects of water contamination is predicated upon the coupling of the rapid hydrolysis reactions of lipophilic cyclic geminal ethers, with the concomitant prodn. of a hydrophilic acyclic hydroxyester with de-icing properties (Fuel Dehydrating Icing Inhibitors - FDII). To this end, a kinetic appraisal of the hydrolysis reactions of representative geminal ethers was undertaken using a convenient surrogate for the fuel-water interface (D2O/CD3CN 1:4). We present here a library of acyclic and five/six-membered cyclic geminal ethers arranged according to their hydroxonium catalytic coeffs. for hydrolysis, providing for the first time a framework for the development of FDII. A combination of 1H NMR, labeling and computational studies was used to assess the effects that may govern the obsd. relative rates of hydrolyzes.(h) Salomaa, P.; Kankaanpera, A.; Norin, T. The hydrolysis of 1,3-dioxolan and its alkyl-substituted derivatives. Part I. the structural factors influencing the rates of hydrolysis of a series of methyl-substituted dioxolans. Acta Chem. Scand. 1961, 15, 871– 878, DOI: 10.3891/acta.chem.scand.15-0871[Crossref], [CAS], Google Scholar.15hhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF38XksV2huro%253D&md5=05e33d8429eaa0c3314c051bc00d1749Hydrolysis of 1,3-dioxolane and its alkyl-substituted derivatives. I. Structural factors influencing the rates of hydrolysis of a series of methyl-substituted dioxolanesSalomaa, Pentti; Kankaanpera, AlpoActa Chemica Scandinavica (1961), 15 (), 871-8CODEN: ACHSE7; ISSN:0904-213X.The exptl. techniques for the rate studies were dilatometric, for dioxolane derivs. which carried one or two Me groups at the 2-position, and titrimetric, for those derivs. that did not carry substituents at the 2-position. Based on the magnitude of the activation entropies, it was probable that the dioxolanes hydrolyzed by essentially the same mechanism as acyclic acetals. The introduction of a methyl group at the 2-position increased the rate of hydrolysis of dioxolanes by a factor of 103-104, primarily due to low activation energies. A second Me group at the 2-position increased the rate by another power of 10. The addn. of one or more Me groups as substituents at the 4- and 5-position had a more complex influence on the rate of hydrolysis, most likely because of interaction of steric strain and polar effects. The polar factors involved were similar to those observed in acyclic acetals. The steric strain considerations which involved the partial 2,3-double bond after proton uptake at the 1-position also permitted distinguishing between cis- and trans-2,4-dimethyl-1,3-dioxolane, the cis form hydrolyzing about 4 times faster than the trans form.(i) Jacques, S. A.; Leriche, G.; Mosser, M.; Nothisen, M.; Muller, C. D.; Remy, J.-S.; Wagner, A. From solution to in-cell study of the chemical reactivity of acid sensitive functional groups: a rational approach towards improved cleavable linkers for biospecific endosomal release. Org. Biomol. Chem. 2016, 14, 4794– 4803, DOI: 10.1039/C6OB00846A[Crossref], [PubMed], [CAS], Google Scholar15ihttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XnsVaisL4%253D&md5=b22f2d7b9ab4902cac27f8bfc474aee1From solution to in-cell study of the chemical reactivity of acid sensitive functional groups: a rational approach towards improved cleavable linkers for biospecific endosomal releaseJacques, Sylvain A.; Leriche, Geoffray; Mosser, Michel; Nothisen, Marc; Muller, Christian D.; Remy, Jean-Serge; Wagner, AlainOrganic & Biomolecular Chemistry (2016), 14 (21), 4794-4803CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)PH-Sensitive linkers designed to undergo selective hydrolysis at acidic pH compared to physiol. pH can be used for the selective release of therapeutics at their site of action. In this paper, the hydrolytic cleavage of a wide variety of mol. structures that have been reported for their use in pH-sensitive delivery systems was examd. A wide variety of hydrolytic stability profiles were found among the panel of tested chem. functionalities. Even within a structural family, a slight modification of the substitution pattern has an unsuspected outcome on the hydrolysis stability. This work led us to establish a first classification of these groups based on their reactivities at pH 5.5 and their relative hydrolysis at pH 5.5 vs. pH 7.4. From this classification, four representative chem. functions were selected and studied in-vitro. The results revealed that only the most reactive functions underwent significant lysosomal cleavage, according to flow cytometry measurements. These last results question the acid-based mechanism of action of known drug release systems and advocate for the importance of an in-depth structure-reactivity study, using a tailored methodol., for the rational design and development of bio-responsive linkers.
- 16Blanco-Ania, D.; Rutjes, F. P. J. T. Carbonylonium ions: the onium ions of the carbonyl group. Beilstein J. Org. Chem. 2018, 14, 2568– 2571, DOI: 10.3762/bjoc.14.233[Crossref], [PubMed], [CAS], Google Scholar16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitVKit7%252FO&md5=58b4ec63a878f46fcdf0a1cb1430f301Carbonylonium ions: the onium ions of the carbonyl groupBlanco-Ania, Daniel; Rutjes, Floris P. J. T.Beilstein Journal of Organic Chemistry (2018), 14 (), 2568-2571CODEN: BJOCBH; ISSN:1860-5397. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)The nomenclature of cations R1C(=O+R3)R2 (R1, R2, R3 = H or organyl) has been examd. and shown to be in a state of immeasurable confusion: a pragmatic recommendation is made that the generic term "carbonylonium ions" should be adopted for these intermediates, which comprises the terms "aldehydium" (R1 = H, R2, R3 = H or organyl) and "ketonium ions" (R1, R2 = organyl, R3 = H or organyl) for the corresponding aldehyde- and ketone-based intermediates, resp.
- 17(a) Fife, T. H.; Hagopian, L. Steric effects in ketal hydrolysis. J. Org. Chem. 1966, 31, 1772– 1775, DOI: 10.1021/jo01344a024[ACS Full Text.], [CAS], Google Scholar17ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF28Xkt1Sjurs%253D&md5=02c3007410650211c380581d63381f60Steric effects in ketal hydrolysisFife, Thomas H.; Hagopian, LilyJournal of Organic Chemistry (1966), 31 (6), 1772-5CODEN: JOCEAH; ISSN:0022-3263.The rates of acid-catalyzed hydrolysis of diethyl ketal and 2,2-disubstituted 1,3-dioxolane derivs. of both aromatic and aliphatic ketones have been measured in 50% dioxane-H2O at 30°. The 1,3-dioxolane derivs. of BzMe and BzEt hydrolyze considerably slower than 2-phenyl-1,3-dioxolane, whereas the diethyl ketal derivs. of these ketones hydrolyze much faster than does BzH diethyl acetal, indicating the presence of a large steric retardation of the rate of hydrolysis of the 2-phenyl-2-alkyl-1,3-dioxolanes. The rates of hydrolysis of 2,2-dialkyl-1.3-dioxolanes appear to be subject to smaller steric effects. The observed retardations in rate are assocd. with less favorable ΔH* values. Values of ΔS* are nearly const. for all of the 2-phenyl-1,3-dioxolanes. A const. ΔS* difference of 8-10 e.u. appears to exist between 1,3-dioxolanes and the corresponding diethyl acetal or ketal regardless of substitution at the 2-position.(b) McClelland, R. A.; Watada, B.; Lew, C. S. Q. Reversibility of the ring-opening step in the acid hydrolysis of cyclic acetophenone acetals. J. Chem. Soc., Perkin Trans. 2 1993, 1723– 1727, DOI: 10.1039/p29930001723[Crossref], [CAS], Google Scholar.17bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXktlCmt7Y%253D&md5=37a6d2e3e80a6a8abf2fccea6d28c14aReversibility of the ring-opening step in the acid hydrolysis of cyclic acetophenone acetalsMcClelland, Robert A.; Watada, Brian; Lew, Calvin S. Q.Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999) (1993), (10), 1723-7CODEN: JCPKBH; ISSN:0300-9580.The acid-catalyzed hydrolysis of the vinyl ethers α-(3-hydroxyethoxy)styrene 1a or α-(3-hydroxypropoxy)styrene 1b yields a mixt. of acetophenone and a cyclic acetophenone acetal, 2-methyl-2-phenyl-1,3-dioxolane3a or 2-methyl-2-phenyl-1,3-dioxane 3b. The [acetophenone]:[3] ratios, detd. by HPLC and UV, are 15 from 1a and 10 from 1b. The acetals undergo further hydrolysis, but this is considerably slower than that of the vinyl ethers, and the above nos. represent products of kinetics control. These product ratios are equal to the rate const. ratios k2:k-1 for the partitioning of the oxocarbocations 1-(2-hydroxyethoxy)-1-phenylethyl 2a of 1-(3-hydroxypropoxy)-1-phenylethyl 2b between reaction with solvent water mols. and with the internal hydroxy group. These cations are also formed as intermediates in the hydrolysis of the cyclic acetals 3. That k2 is an order of magnitude greater than k-1 signifies that the rate-limiting step in this hydrolysis is the ring-opening forming the oxocarbocation, and that there is little reversibility in aq. solns. The hydrolysis reactions of these cyclic acetals are considerably slower than that of an acyclic analog, the di-Me acetal of acetophenone, by factors of 1.0 × 103 for 3a and 1.8 × 102 for 3b. This study demonstrates that these rate retardations cannot be accounted for by reversibility of the ring-opening step. The presence of the ring results in an inherent decrease in the rate const. for the H+-catalyzed formation of the oxocarbocation.(c) Knowles, J. P.; Whiting, A. The effects of ring size and substituents on the rates of acid-catalysed hydrolysis of five- and six-membered ring cyclic ketone acetals. Eur. Eur. J. Org. Chem. 2007, 2007, 3365– 3368, DOI: 10.1002/ejoc.200700244 .(d) Liu, B.; Thayumanavan, S. Substituent effects on the pH sensitivity of acetals and ketals and their correlation with encapsulation stability in polymeric nanogels. J. Am. Chem. Soc. 2017, 139, 2306– 2317, DOI: 10.1021/jacs.6b11181[ACS Full Text], [CAS], Google Scholar17dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsVagt78%253D&md5=b265a1435bcc42b4fce000034d13d279Substituent Effects on the pH Sensitivity of Acetals and Ketals and Their Correlation with Encapsulation Stability in Polymeric NanogelsLiu, Bin; Thayumanavan, S.Journal of the American Chemical Society (2017), 139 (6), 2306-2317CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)The effect of structural variations in acetal- and ketal-based linkers upon their degrdn. kinetics is studied through the design, synthesis, and study of six series of mols., comprising a total of 18 different mols. Through this systematic study, the structural fine-tuning of the linkers allows access to variations in kinetics of degrdn. of >6 orders of magnitude. Hammett correlations show that the ρ value for the hydrolysis of benzylidene acetals is ∼-4.06, which is comparable to an SN1-like process. There is a strong, developing pos. charge at the benzylic position in the transition state during the degrdn. of acetals. This pos. charged transition state is consistent with the relative degrdn. rates of acetals vs. ketals (correlated to stabilities of 1°, 2°, and 3° carboxonium ion type intermediates) and the obsd. effect of proximal electron-withdrawing groups upon the degrdn. rates. Following this, the authors studied whether the degrdn. kinetics study correlates with pH-sensitive variations in the host-guest characteristics of polymeric nanogels that contains these acetal or ketal moieties as crosslinking functionalities. Indeed, the trends obsd. in the small mol. degrdn. have clear correlations with the encapsulation stability of guest mols. within these polymeric nanogels. The implications of this fundamental study extend to a broad range of applications, well beyond the polymeric nanogel examples studied here.
- 18Miller, S. R.; Krasutsky, S.; Kiprof, P. Stability of carboxonium ions. J. Mol. Struct.: THEOCHEM 2004, 674, 43– 47, DOI: 10.1016/j.theochem.2003.12.044[Crossref], [CAS], Google Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXjsVCkt7s%253D&md5=4377259364607f8273f0f65712a0d3edStability of carboxonium ionsMiller, Stephen R.; Krasutsky, Sergiy; Kiprof, PaulJournal of Molecular Structure: THEOCHEM (2004), 674 (1-3), 43-47CODEN: THEODJ; ISSN:0166-1280. (Elsevier Science B.V.)Carboxonium ions were studied through anal. of the bonding situation in terms of natural bond order, natural resonance structure contributors and charges. The stabilizing effect of oxygen was also elucidated through hydride exchange reactions and study of the π interactions of the cationic carbon with oxygen substituents.
- 19Carey, F. A.; Sundberg, R. J. Reaction of Carbonyl Compounds. Advanced Organic Chemistry 1977, 325– 360, DOI: 10.1007/978-1-4613-9792-2_8
- 20(a) Guthrie, J. P. Carbonyl addition reactions. Factors affecting the hydrate-hemiacetal and hemiacetal-acetal equilibrium constants. Can. J. Chem. 1975, 53, 898– 906, DOI: 10.1139/v75-125[Crossref], [CAS], Google Scholar.20ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE2MXlsVKru70%253D&md5=230f58d8019ca38412534a1ed11781dfCarbonyl addition reactions. Factors affecting the hydrate-hemiacetal and hemiacetal-acetal equilibrium constantsGuthrie, J. PeterCanadian Journal of Chemistry (1975), 53 (6), 898-905CODEN: CJCHAG; ISSN:0008-4042.Equil. consts. for hydrate-hemiacetal interconversion in aq. soln. at 25° have been measured for four fluorinated carbonyl compds.: compd., alc., K4 (M-1): CF3CHO, EtOH, 2.3; CF3COMe, MeOH, 1.0; CF3COPh, MeOH, 3.5; CF3COCF3, MeOH, 0.14. These values, combined with values from the literature, permitted an examn. of substituent effects upon the equil. const. for C-OH + ROH ↹ C-OR + H2O. The free energy change for this process, corrected for symmetry and steric effects, followed the equation ΔG4'' = -0.54 + 0.63 Σσ*. Electronic effects upon this equil. were generally small and in fact were often smaller than steric effects. This anal. permitted calcn. of free energies of formation of C-OH compds. from the free energies of formation of the analogous C-OR compds.(b) Greenzaid, P.; Luz, Z.; Samuel, D. A nuclear magnetic resonance study of the reversible hydration of aliphatic aldehydes and ketones. I. Oxygen-17 and proton spectra and equilibrium constants. J. Am. Chem. Soc. 1967, 89, 749– 756, DOI: 10.1021/ja00980a004[ACS Full Text], [CAS], Google Scholar20bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF2sXmsV2juw%253D%253D&md5=0cbf3d1e2957789d34b12aaea9da3a4eA nuclear magnetic resonance study of the reversible hydration of aliphatic aldehydes and ketones. I. Oxygen-17 and proton spectra and equilibrium constantsGreenzaid, Peniel; Luz, Zeev; Samuel, DavidJournal of the American Chemical Society (1967), 89 (4), 749-56CODEN: JACSAT; ISSN:0002-7863.17O N.M.R. spectra of aq. solns. of a no. of aliphatic carbonyl compds. enriched in 17O are reported. The resonances of the unhydrated carbonyl species and of the hydrated gem-diol species fall in two different regions. The carbonyl O resonance falls in the range -520 to -560 ppm. (relative to H217O), and that of the gem-diol falls close to the water line, often being concealed by it. P.M.R. spectra were also studied and used to det. equil. consts., Kd, for the hydration-dehydration reaction of the carbonyl group. A good correlation between Kd values, which span a range of seven orders of magnitude, and Σσ* is obtained provided account is taken of the no. of aldehydic protons in the mol. The following free-energy relationship between Kd and Σσ* is proposed, -log Kd = ρ* Σσ* + BΔ + C, where ρ*, B, and C are consts., and Δ is the no. of aldehydic hydrogens in the mol. A best-fit analysis gave ρ* = 1.70 ± 0.07, B = 2.03 ± 0.10, and C = -2.81 ± 0.13. These results are discussed in terms of adjacent bond interaction. 28 references.
- 21Butler, T. C. The introduction of chloral hydrate into medical practice. Bull. Hist. Med. 1970, 44, 168– 172[PubMed], [CAS], Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaE3c3ktVShsw%253D%253D&md5=cb658517712333264738af5be072a435The introduction of chloral hydrate into medical practiceButler T CBulletin of the history of medicine (1970), 44 (2), 168-72 ISSN:0007-5140.There is no expanded citation for this reference.
- 22(a) West, R. Siegfried Ruhemann and the discovery of ninhydrin. J. Chem. Educ. 1965, 42, 386– 388, DOI: 10.1021/ed042p386[ACS Full Text.], [CAS], Google Scholar22ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF2MXkt1Onu7s%253D&md5=cb1388b8bc927de60fc642c5e49a152aSiegfried Ruhemann and the discovery of ninhydrinWest, RobertJournal of Chemical Education (1965), 42 (7), 386-7CODEN: JCEDA8; ISSN:0021-9584.A biographical review.(b) Odén, S.; von Hofsten, B. Detection of fingerprints by the ninhydrin reaction. Nature 1954, 173, 449– 450, DOI: 10.1038/173449a0[Crossref], [PubMed], [CAS], Google Scholar22bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaG2cXjvVOrtw%253D%253D&md5=50d1fa5ba15d6e398cdc5d8134c8c41fDetection of fingerprints by the ninhydrin reactionOden, Svante; v. Hofsten, BengtNature (London, United Kingdom) (1954), 173 (), 449-50CODEN: NATUAS; ISSN:0028-0836.A spontaneous fingerprint contains 98.5-99.5% H2O, the rest being org. and inorg. compds. Normally, the H2O will evap. leaving the rest as a fingerprint pattern contg. fats, salts, amino acids, etc. The amino acids give the well known color reaction with ninhydrin. This offers a good method for detecting fingerprints on paper and similar materials. Fingerprints are developed by spraying the paper with a 0.2% soln. of ninhydrin in acetone, followed by heating in an oven at 80° for a few min. This initiates the process, and the pink color becomes more intense with time and new marks appear as the developing process matures. Details have a max. distinctness a day or two after the ninhydrin treatment.
- 23Simmons, H. E.; Wiley, D. W. Fluoroketones. J. Am. Chem. Soc. 1960, 82, 2288– 2296, DOI: 10.1021/ja01494a047[ACS Full Text], [CAS], Google Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF3cXhtFSmtLo%253D&md5=c61f15a230dee2aa651333cd718be719Fluoro ketones. ISimmons, Howard E., Jr.; Wiley, Douglas W.Journal of the American Chemical Society (1960), 82 (), 2288-96CODEN: JACSAT; ISSN:0002-7863.(CClF2)2CO (I) (CCl2F)2CO (II), (CF3)2CO (III), and CF3Ac (IV) were converted by a novel base-catalyzed ketalization to ketals of unusual thermal and chem. stability; this synthesis was also extended to dioxolanes, dioxanes, oxazolidines, oxathiolanes, and their carbonyl-contg. analogs. The fluoro ketones react with CH2N2 to give high yields of stable epoxides and condense readily with active methylene compds. and metallic acetylides. I and NH3 gave 100% (CClF2)2C(OH)NH2, m. 67-8°. I (25.0 g.) treated slowly with stirring with 5.8 g. abs. EtOH followed by 15.9 g. Me2SO4, and finally by 15 g. K2CO3 in small portions during 1 hr. while small amts. of pentane were added to keep the mixt. fluid, the mixt. poured after 4 hrs. into 100 cc. cold H2O, and the product isolated with pentane gave 15.1 g. (CClF2)2C(OMe)OEt (V), b51 79-80°, n25D 1.3857, also obtained in 25% yield by alkylating (CClF2)2C(OH)OEt (VI) with MeI and Ag2O. Similarly were prepd. the following (CClF2)C(OMe)OR (R, b.p./mm., n25D, and % yield given): Me, 147-8°/760, 1.3829, 47; EtMeCH, 71.5°/15, 1.3965, 40; C3F7CH2, 73°/25, 1.3406, 61; H(CF2)10CH2, 150-4°/12, 1.3395, 48. (C3F7)2C(OMe)2 b. 72-3°/48, 1.3105, 92. I (50.0 g.) and 20.2 g. Cl(CH2)2OH (VII) stirred 15 min., dild. with 50 cc. pentane, treated with 35 g. K2CO3 in portions during 1 hr., stirred 2 hrs., and poured into H2O, the aq. phase extd. with pentane, and the combined org. phase and ext. fractionated gave 51.3 g. 2,2-bis(chlorodifluoromethyl)-1,3-dioxolane (VIII), b. 171-2°, n25D 1.3896, also obtained in 30% yield by adding an equimolar mixt. of I and VII to 15% aq. KOH and extg. with pentane. Similarly were prepd. the following compds. (b.p./mm., n25D, and % yield given): 2,2-bis(trifluoromethyl)-1,3-dioxolane, 99-100°/760, 1.3088, 16 (from III); 2,2-bis(dichlorofluoromethyl)-1,3-dioxolane, 65-6°/l, 1.4680, 42 (from II); 2-trifluoromethyl-1,3-dioxolane, 92°/760, 1.3353, 11; 2,2-bis(chlorodifluoromethyl)4-chloromethyl-1,3-dioxolane, 74°/6, 1.4171, 88, 2,2-bis(chlorodifluoromethyl)-1,3-dioxane, 112-13°/50, 1.4109, 37. (CCl3)2CO (20.0 g.), 9.2 g. VII, 15.6 g. K2CO3, and 60 cc. pentane stirred at room temp. overnight, poured into 100 cc. H2O, and extd. with pentane, and the ext. worked up gave 15.1 g. CCl3CO2(CH2)2Cl, b0.2 57°, n25D 1.4782. IV (25.0 g.) and 18.0 g. VII treated with 30.8 g. K2CO3 in portions during 1 hr. with stirring and cooling, stirred 4 hrs. at room temp., and poured into 150 cc. H2O, and the product isolated with pentane gave 28 g. crude product which fractionated yielded 13 g. 5,7-bis(trifluoromethyl)-5-hydroxy-7-methyl-1,4-dioxacycloheptane (IX), b11 69-70°, n25D 1.3675, and 12 g. 2,4-dihydroxy-6-methyl-2,4,6-tris(trifluoromethyl)pyran (X), b10 77-8°, m. 107-8° (pentane). IX and X form salts with LiH in Et2O. I (120 g.) treated during 10 min. with stirring and cooling with 33.6 g. CH.tbd.CCH2OH, b. 113-15°, the mixt. treated with 2 g. yellow HgO in 4 portions at 5-min. intervals, kept 4 hrs. at 35°, and fractionated gave 129 g. 4-methylene deriv. of VIII, b13 51-3°, n25D 1.3982, d2525 1.514. CH.tbd.C(CH2)2OH yielded similarly 74% 2,2-bis(chlorodifluoromethyl)-4-methylene-1,3-dioxane, b22 86-8°, n25D 1.4192, d25 1.505. VIII (24.3 g.) in 200 cc. CCl4 treated with stirring and irradiation with a sunlamp during 3 hrs. with 7.1 g. Cl and fractionated gave 18.0 g. 4-Cl deriv. of VIII, b750 179-80°, n25D 1.4050, 1.4093, d25 1.657, 1.669. Similar runs with more Cl and at higher temps. gave the following derivs. of VIII (substituents, b.p./750 mm., n25D, and d25 given): 4,5(or 4,4)-di-Cl, 182-4°, 1.4159, 1.692; 4,4,5-tri-Cl, 199-200°, 1.4319, 1.755; 4,4,5,5-tetra-Cl, 218-19°, 1.4466, 1.811. I (25.0 g. in 50 cc. dry Et2O treated dropwise with stirring with 10.7 g. piperidine in 50 cc. dry Et2O at -20°, the mixt. treated successively with 15.9 g. Me2SO4 and 15 g. K2CO3, warmed to room temp., stirred overnight, dild. with H2O, and extd. with Et2O, and the ext. worked up gave 2.5 g. 1-(chlorodifluoroacetyl)piperidine, b0.55 63°, n25D 1.4512, also obtained in 62% yield at 0°. Br(CH2)2NH2 (41.0 g.) in 75 cc. HCONMe2 treated with cooling with 79.6 g. I, the mixt. treated during 1 hr. with 55.4 g. K2CO3 in small portions, stirred 2 hrs., poured into 400 cc. H2O, and extd. with Et2O, and the ext. worked up gave 40.8 g. 2,2-bis(chlorodifluoromethyl)-1,3-oxazolidine (X), b177 138-9°, n25D 1.4122, d25 1.596; X was sol. in concd. H2SO4; it formed with dry HCl a salt which reverted to X by shaking with H2O. I (80 g.) added slowly with cooling and stirring to 19.3 g. Cl(CH2)2SH in 50 cc. Et2O, the mixt. treated with a trace NaOMe, stirred 1 hr., treated with 27.6 g. K2CO3, poured into H2O, and extd. with Et2O, and the ext. worked up gave 17.3 g. 2,2-bis(chlorodifluoromethyl)-1,3-oxathiolane (XI), b9 76°, n25D 1.4414. HOCH2CO2H (30.4 g.) in 50 cc. HCONMe2 treated with 89.0 g. I with stirring and cooling, the mixt. treated with 1 g. NaOAc, kept 3 days, and poured into 1 l. H2O, and the product isolated with CH2Cl2 yielded 52.7 g. 4-oxo deriv. (XII) of VIII, b. 159-61°, n25D 1.3870. Me2C(OH)CO2Et (25.4 g.) added with cooling and stirring to 39.8 g. I in 75 cc. Et2O, treated with 2 g. NaOAc, stirred 48 hrs., filtered, and fractionated gave 24.1 g. VI, b. 108°, n25D 1.3837, and 18.2 g. 5,5-di-Me deriv. of XII, b. 169°, n25D 1.3925. In the same manner as XII was prepd. the 5-oxo deriv. of XI, b50 120°, n25D 1.4388, d25 1.706, in 49% yield. DL-Alanine (13.4 g.) and 60.0 g. I treated with 50 cc. HCONMe2, heated 3 hrs. at 60°, dissolved in 85 cc. CH2Cl2, and poured into 850 cc. H2O, and the product isolated with CH2Cl2 gave 33.2 g. 5-oxo deriv. of X, b16 104°, n25D 1.4099, d25 1.065. H2NCH2CO2H and I gave similarly a crude product which decompd. extensively during an attempted distn. with the formation of HF and CO2. I (90.0 g.) added dropwise during 2 hrs. at 0° to 0.45 mole CH2N2 in 800 cc. Et2O and fractionated yielded 74.0 g. 2,2-bis(chlorodifluoromethyl)oxirane (XIII), b. 106-7°, n25D 1.3670. II and CH2N2 gave similarly 2,2-bis(dichlorofluoromethyl)oxirane, b30 90-1°, n25D 1.4522. (C3F7)2CO and CH2N2 yielded 2,2-bis(heptafluoropropyl)oxirane, b. 120-1°, n25D 1.2932. XIII (10.0 g.) and 9 cc. 46% aq. HBr stirred over a weekend, refluxed several hrs., neutralized with 10% aq. NaHCO3, and extd. with Et2O, and the ext. worked up gave 3.4 g. unchanged XIII and 4.7 g. (CClF2)2C(OH)CH2Br, b. 167-9°, n25D 1.4303. I (25.0 g.) and 14.2 g. NCCH2CO2Et kept 15 min., treated with 20.0 g. AcCl and then during 45 min. with stirring with 10 cc. C5H5N, stirred 0.5 hr., warmed 15 min. on the steam bath, and poured into 125 cc. iced H2O, and the product isolated with pentane gave 20.6 g. (CClF2)2C:C(CN)CO2Et, b0.2 47-8°, n25D 1.4182. Na (28.8 g.) in 300 cc. dry NH3 treated with C2H2, the NH3 displaced with 300 cc. dry Et2O, the mixt. treated dropwise with stirring during 2 hrs. with 200 g. I in 100 cc. dry Et2O, stirred overnight, and dild. with 200 cc. H2O, the aq. phase extd. with Et2O, and the combined Et2O solns. worked up yielded 180 g. (CClF2)2C(OH)C.tbd.CH (XIV), b16 41-2°, n25D 1.3940, pKA 8.92, 8.95 (50% aq. EtOH). III and Na2C2 yielded similarly 16% (CF3)2C(OH)C.tbd.CH (XV), b. 87-8°, n25D 1.3125. EtBr (82.0 g.), 20.2 g. Mg, and 240 cc. dry Et2O treated with stirring with C2H2, the mixt. treated dropwise during 1 hr. with stirring and cooling with 100 g. I in 100 cc. dry Et2O, stirred 24 hrs. at room temp., and treated with cooling with 200 cc. 5N HCl, and the product isolated with Et2O gave 20.5 g. XIV, b18 40-1°, n25D 1.3862; the pot residue recrystd. from Et2O yielded 56.4 g. [.tbd.CC(CClF2)2OH]2, (XVI), m. 51-2°, pKA1 7.35, 7.45, pKA2 10.03, 10.05 (50% aq. EtOH). XIV (15.0 g.) and 7.9 g. AcCl treated at 0° dropwise with stirring with 6 cc. C5H5N, stirred 2 hrs. at 0°, and dild. with 100 cc. iced H2O, and the product isolated with pentane yielded 16.5 g. acetate of XIV, b14 66-7°, n25D 1.4031. XIV (10.00 g.) in 10 cc. dry C6H6 added dropwise with stirring to 1.06 g. NaH in 60 cc. dry C6H6, stirred 0.5 hr., refluxed 2 days with 8.48 g. p-MeC6H4SO2Cl, washed with 5% aq. NaHCO3 and H2O, dried, and distd., and the distillate (11.2 g.) sublimed gave the 3-(p-toluenesulfonate) of XIV, m. 43-4°. Similarly were prepd. the 3-(p-toluenesulfonate) of XV, m. 36-7° (pentane), 78%, and the 1,4-bis(p-toluenesulfonate) of XVI, m. 189-90° (Me2CO), 75%. I (4.7 g.), 5.0 g. XVI, 3.0 g. Me2SO4, and 1.4 g. K2CO3 stirred 20 hrs. at room temp., the mixt. poured into 100 cc. H2O, and the product isolated with pentane gave 2.5 g. di-Me ether of XVI, b0.2 67°, n25D 1.4061. XIV (22.5 g.), 25.0 g. CuCl, 40.0 g. NH4Cl, and 100 cc. H2O shaken 1 hr. and extd. with Et2O, and the ext. worked up gave 11.5 g. [C.tbd.CC(OH)(CClF2)2]2, m. 79-80° (sublimed). XIV (50.0 g.) and 52.0 g. PCl5 heated 1 hr. on the steam bath, poured onto 400-500 g. crushed ice, and shaken 2 min., and the product isolated with 200 cc. pentane gave 4.3 g. unchanged XIV and 26.6 g. CF2:C(CClF2)CCl:CHCl, b38 43°, n25D 1.4152. XVI (10.0 g.) and 9.8 g. PCl5 refluxed 0.5 hr., and poured onto 200-300 g. crushed ice, the mixt. shaken 2 min., the org. phase extd. with hexane, and the ext. worked up yielded 6.0 g. (CClF2)2CClC≡CC(OH)(CClF2)2, b1.7 69-70°, n25D 1.4300.
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- 28Maryanoff, B. E.; Costanzo, M. J.; Nortey, S. O.; Greco, M. N.; Shank, R. P.; Schupsky, J. J.; Ortegon, M. P.; Vaught, J. L. Structure-activity studies on anticonvulsant sugar sulfamates related to topiramate. Enhanced potency with cyclic sulfate derivatives. J. Med. Chem. 1998, 41, 1315– 1343, DOI: 10.1021/jm970790w[ACS Full Text], [CAS], Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXitFGju7o%253D&md5=d79f854b98ec4de7b065af4e42d3be59Structure-Activity Studies on Anticonvulsant Sugar Sulfamates Related to Topiramate. Enhanced Potency with Cyclic Sulfate DerivativesMaryanoff, Bruce E.; Costanzo, Michael J.; Nortey, Samuel O.; Greco, Michael N.; Shank, Richard P.; Schupsky, James J.; Ortegon, Marta P.; Vaught, Jeffry L.Journal of Medicinal Chemistry (1998), 41 (8), 1315-1343CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The authors have explored the structure-activity relationship (SAR) surrounding the clin. efficacious antiepileptic drug topiramate (I), a unique sugar sulfamate anticonvulsant that was discovered in our labs. Systematic structural modification of the parent compd. was directed to identifying potent anticonvulsants with a long duration of action and a favorable neurotoxicity index. In this context, we have probed the pharmacol. importance of several mol. features: (1) the sulfamate group, (2) the linker between the sulfamate group and the pyran ring, (3) the substituents on the 2,3- and 4,5-fused 1,3-dioxolane rings, (4) the constitution of the 4,5-fused 1,3-dioxolane ring, (5) the ring oxygen atoms, and (6) the abs. stereochem. The authors established the C1 configuration as R for the predominant alc. diastereomer from the highly selective addn. of methylmagnesium bromide to aldehyde by single-crystal X-ray anal. of the major diastereomer of sulfamate. Details for the stereoselective syntheses of the hydrindane carbocyclic analogs are presented. The authors also report the synthesis of cyclic imidosulfites and imidosulfate, which are rare examples in the class of such five-membered-ring sulfur species. Imidosulfite required the prepn. and use of the novel sulfur dichloride reagent, BocN:SCl2. Our SAR investigation led to the impressive 4,5-cyclic sulfate analog (II) (RWJ-37947), which exhibits potent anticonvulsant activity in the maximal electroshock seizure (MES) test (ca. 8 times greater than I in mice at 4 h, ED50 = 6.3 mg/kg; ca. 15 times greater than I in rats at 8 h, ED50 = 1.0 mg/kg) with a long duration of action (>24 h in mice and rats, po) and very low neurotoxicity (TD50 value of >1000 mg/kg at 2 h, po in mice). Cyclic sulfate II, like topiramate and phenytoin, did not interfere with seizures induced by pentylenetetrazole, bicucculine, picrotoxin, and strychnine; also, II was not active in diverse in vitro receptor binding and uptake assays. However, II turned out to be a potent inhibitor of carbonic anhydrase from different rat tissue sources (e.g., IC50 of 84 nM for the blood enzyme and 21 nM for the brain enzyme). An examn. of several analogs of II indicated that potent anticonvulsant activity is assocd. with relatively small alkyl substituents on nitrogen (Me/H, Me/Me, Et/H, allyl/H, c-Pr/H, c-Bu/H,) and with limited changes in the cyclic sulfate group, such as 4,5-cyclic sulfite. The potent anticonvulsants had greatly diminished carbonic anhydrase inhibitory activity; thus, inhibition of this enzyme may not be a significant factor in the anticonvulsant activity. The α-L-sorbopyranoses, which mainly possess a skew conformation (ref 29), were nearly twice as potent as I. The L-fructose ent-I and ent-II, synthesized from L-sorbose, were found to have moderate anticonvulsant activity, with eudysmic ratios (MES ED50 in mice at 4 h, po) of I:ent-I = 1.5 and II:ent-II = 8.0. Log P values for I and II were detd. exptl. to be 0.53 and 0.42, resp., which are less than the optimal 2.0 for CNS active agents. However, analogs with more favorable calcd. log P (clogP) values, in conjunction with just minor steric perturbation according to the developed SAR profile did not display improved potency. Although the measured log P value for di-Et is 1.52, this did not translate into enhanced potency relative to I. The 400-MHz 1H NMR studies of I and II indicated that the skew 3S0 conformer predominates at ambient temp. in nonaq. and aq. media; hydrindane (III) strongly populates a skew 3S0 conformer in benzene. X-ray crystal structures for I, II, and III depict the skew 3S0 conformer in the solid state. Soln. IR studies showed an absence of intramol. hydrogen bonding, in contrast to what has been obsd. for alc. 4 (ref 73).
- 29Rankovic, Z. CNS drug design: balancing physicochemical properties for optimal brain exposure. J. Med. Chem. 2015, 58, 2584– 2608, DOI: 10.1021/jm501535r[ACS Full Text], [CAS], Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitVyhsrrP&md5=f01e3f2dc4e2eff7b0618124277a5cf8CNS Drug Design: Balancing Physicochemical Properties for Optimal Brain ExposureRankovic, ZoranJournal of Medicinal Chemistry (2015), 58 (6), 2584-2608CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. The human brain is a uniquely complex organ, which has evolved a sophisticated protection system to prevent injury from external insults and toxins. Designing mols. that can overcome this protection system and achieve optimal concn. at the desired therapeutic target in the brain is a specific and major challenge for medicinal chemists working in CNS drug discovery. Analogous to the now widely accepted rule of 5 in the design of oral drugs, the physicochem. properties required for optimal brain exposure have been extensively studied in an attempt to similarly define the attributes of successful CNS drugs and drug candidates. This body of work is systematically reviewed here, with a particular emphasis on the interplay between the most crit. physicochem. and pharmacokinetic parameters of CNS drugs as well as their impact on medicinal chem. strategies toward mols. with optimal brain exposure. A summary of modern CNS pharmacokinetic concepts and methods is also provided.
- 30Brand, S.; Norcross, N. R.; Thompson, S.; Harrison, J. R.; Smith, V. C.; Robinson, D. A.; Torrie, L. S.; McElroy, S. P.; Hallyburton, I.; Norval, S.; Scullion, P.; Stojanovski, L.; Simeons, F. R.; Aalten, D. V.; Frearson, J. A.; Brenk, R.; Fairlamb, A. H.; Ferguson, M. A.; Wyatt, P. G.; Gilbert, I. H.; Read, K. D. Lead optimization of a pyrazole sulfonamide series of Trypanosoma brucei N-!myristoyltransferase inhibitors: identification and evaluation of CNS penetrant compounds as potential treatments for stage 2 human African trypanosomiasis. J. Med. Chem. 2014, 57, 9855– 9869, DOI: 10.1021/jm500809c[ACS Full Text], [CAS], Google Scholar30https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvFKqu7rP&md5=6d6f5e8618aa3b7017b789f89d9540a5Lead Optimization of a Pyrazole Sulfonamide Series of Trypanosoma brucei N-Myristoyltransferase Inhibitors: Identification and Evaluation of CNS Penetrant Compounds as Potential Treatments for Stage 2 Human African TrypanosomiasisBrand, Stephen; Norcross, Neil R.; Thompson, Stephen; Harrison, Justin R.; Smith, Victoria C.; Robinson, David A.; Torrie, Leah S.; McElroy, Stuart P.; Hallyburton, Irene; Norval, Suzanne; Scullion, Paul; Stojanovski, Laste; Simeons, Frederick R. C.; van Aalten, Daan; Frearson, Julie A.; Brenk, Ruth; Fairlamb, Alan H.; Ferguson, Michael A. J.; Wyatt, Paul G.; Gilbert, Ian H.; Read, Kevin D.Journal of Medicinal Chemistry (2014), 57 (23), 9855-9869CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Trypanosoma brucei N-myristoyltransferase (TbNMT) is an attractive therapeutic target for the treatment of human African trypanosomiasis (HAT). From previous studies, we identified pyrazole sulfonamide, DDD85646 (1), a potent inhibitor of TbNMT. Although this compd. represents an excellent lead, poor central nervous system (CNS) exposure restricts its use to the hemolymphatic form (stage 1) of the disease. With a clear clin. need for new drug treatments for HAT that address both the hemolymphatic and CNS stages of the disease, a chem. campaign was initiated to address the shortfalls of this series. This paper describes modifications to the pyrazole sulfonamides which markedly improved blood-brain barrier permeability, achieved by reducing polar surface area and capping the sulfonamide. Moreover, replacing the core arom. with a flexible linker significantly improved selectivity. This led to the discovery of DDD100097 (40) which demonstrated partial efficacy in a stage 2 (CNS) mouse model of HAT.
- 31Christensen, J.; Højskov, C. S.; Dam, M.; Poulsen, J. H. Plasma concentration of topiramate correlates with cerebrospinal fluid concentration. Ther. Drug Monit. 2001, 23, 529– 535, DOI: 10.1097/00007691-200110000-00006[Crossref], [PubMed], [CAS], Google Scholar31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXnvVygt7k%253D&md5=528ff03f181f2edcfb4b2b3c9138ffa1Plasma concentration of topiramate correlates with cerebrospinal fluid concentrationChristensen, Jakob; Hojskov, Carsten S.; Dam, Mogens; Poulsen, Jorgen H.Therapeutic Drug Monitoring (2001), 23 (5), 529-535CODEN: TDMODV; ISSN:0163-4356. (Lippincott Williams & Wilkins)The authors examd. the ratio between the plasma and the cerebrospinal fluid (CSF) concn. of topiramate in 14 adults with epilepsy. Simultaneous trough samples of venous blood and CSF were collected and analyzed as total and unbound concns. Concomitant levels were also analyzed of Lamotrigine (n = 5) and the relevant oxcarbazepine metabolite, 10-hydroxycarbazepine (n = 3). There was a close correlation between the plasma and the CSF concn. for both the total and unbound concn. of topiramate. The median CSF/plasma ratio of total topiramate was 0.85. The free topiramate concn. in plasma was not different from the free topiramate concn. in CSF. The CSF/plasma ratios showed little variation and were independent of the plasma level for both the total and the unbound levels. The unbound fraction of topiramate was 84% in plasma and 97% in CSF. The CSF concns. of Lamotrigine and 10-hydroxycarbazepine were 50% and 61% of the plasma concns., resp. For topiramate, there is a close correlation between the plasma concn. and the CSF concn. There does not seem to be a saturable carrier mechanism restricting topiramate transport across the blood-brain barrier. The concn. of topiramate in CSF is equal to the unbound proportion of topiramate in plasma, implying that the delivery of topiramate to the brain occurs via transfer from the unbound plasma pool. Plasma is thus a relevant matrix for therapeutic drug monitoring of topiramate.
- 32Caldwell, G. W.; Wu, W. N.; Masucci, J. A.; McKown, L. A.; Gauthier, D.; Jones, W. J.; Leo, G. C.; Maryanoff, B. E. Metabolism and excretion of the antiepileptic/antimigraine drug, topiramate in animals and humans. Eur. J. Drug Metab. Pharmacokinet. 2005, 30, 151– 164, DOI: 10.1007/BF03190614[Crossref], [PubMed], [CAS], Google Scholar32https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtFCgtLrN&md5=03b77332c0c89dc042dc73672644af70Metabolism and excretion of the antiepileptic/antimigraine drug, topiramate in animals and humansCaldwell, Gary W.; Wu, W. N.; Masucci, J. A.; McKown, L. A.; Gauthier, D.; Jones, W. J.; Leo, G. C.; Maryanoff, B. E.European Journal of Drug Metabolism and Pharmacokinetics (2005), 30 (3), 151-164CODEN: EJDPD2; ISSN:0378-7966. (Medecine et Hygiene)The metab. and excretion of 2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose sulfamate (TOPAMAX, topiramate, TPM) have been investigated in animals and humans. Radiolabeled [14C]TPM was orally administered to mice, rats, rabbits, dogs and humans. Plasma, urine and fecal samples were collected and analyzed. TPM and a total of 12 metabolites were isolated and identified in these samples. Metabolites were formed by hydroxylation at the 7- or 8-Me of an isopropylidene of TPM followed by rearrangement, hydroxylation at the 10-Me of the other isopropylidene, hydrolysis at the 2,3-O-isopropylidene, hydrolysis at the 4,5-O-isopropylidene, cleavage at the sulfamate group, glucuronide conjugation and sulfate conjugation. A large percentage of unchanged TPM was recovered in animal and human urine. The most dominant metabolite of TPM in mice, male rats, rabbits and dogs appeared to be formed by the hydrolysis of the 2,3-O-isopropylidene group.
- 33Patsalos, P. N. The mechanism of action of topiramate. Rev. Contemp. Pharmacother. 1999, 10, 147– 153[CAS], Google Scholar33https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXnslGhsb4%253D&md5=c9aecbe553ce2d32c4725214e574f7c5The mechanism of action of topiramatePatsalos, Philip N.Reviews in Contemporary Pharmacotherapy (1999), 10 (3), 147-153CODEN: RCPHFW; ISSN:0954-8602. (Marius Press)A review with ∼55 refs. As epilepsy is one of the most prominent serious neurol. conditions, affecting about 50 million people world-wide, of whom 20% are pharmacol. intractable, there has been substantial interest in developing new antiepileptic drugs. Since 1989 eight new antiepileptic drugs have been licensed world-wide. Topiramate, a sulfamate-substituted monosaccharide, was licensed in the UK in 1995 as adjunctive therapy in patients with intractable partial epilepsy. Clin. evidence suggests that topiramate is a potent antiepileptic drug with a broad spectrum of activity and corroborates the significant efficacy obsd. in predictive animal models of epilepsy, i.e., maximal electroshock, i.v. pentylenetetrazole, genetic (spontaneous epileptic rat and DBA/2 mouse) and amygdala kindling models. Pharmacol. evidence indicates that topiramate may act via several mechanisms including: modulation of voltage-dependent sodium channels, potentiation of γ-aminobutyric acid (GABA) inhibition, block of excitatory neurotransmission, and possibly modulation of voltage- and receptor-gated calcium ion channels. Topiramate not only prevents seizure spread but it also elevates seizure threshold. Carbonic anhydrase inhibiting properties have also been demonstrated but they are not considered to be relevant to anticonvulsant activity. This combination of pharmacol. properties is unique amongst currently available antiepileptic drugs and may explain why topiramate is effective in both partial and generalized seizures, and why it is proving efficacious in numerous intractable syndromic epilepsies.
- 34(a) Monteiro, J.; Alves, M. G.; Oliveira, P. F.; Silva, B. M. Pharmacological potential of methylxanthines: Retrospective analysis and future expectations. Crit. Rev. Food Sci. Nutr. 2019, 59, 2597– 2625, DOI: 10.1080/10408398.2018.1461607[Crossref], [PubMed], [CAS], Google Scholar.34ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXpslaksbY%253D&md5=af1ec49bae9b7813e0903b0f8f71c55dPharmacological potential of methylxanthines: Retrospective analysis and future expectationsMonteiro, Joao; Alves, Marco G.; Oliveira, Pedro F.; Silva, Branca M.Critical Reviews in Food Science and Nutrition (2019), 59 (16), 2597-2625CODEN: CRFND6; ISSN:1040-8398. (Taylor & Francis, Inc.)Methylated xanthines (methylxanthines) are available from a significant no. of different botanical species. They are ordinarily included in daily diet, in many extremely common beverages and foods. Caffeine, theophylline and theobromine are the main methylxanthines available from natural sources. The supposedly relatively low toxicity of methylxanthines, combined with the many beneficial effects that have been attributed to these compds. through time, generated a justified attention and a very prolific ground for dedicated scientific reports. Methylxanthines have been widely used as therapeutical tools, in an intriguing range of medicinal scopes. In fact, methylxanthines have been/were medically used as Central Nervous System stimulants, bronchodilators, coronary dilators, diuretics and anti-cancer adjuvant treatments. Other than these applications, methylxanthines have also been hinted to hold other beneficial health effects, namely regarding neurodegenerative diseases, cardioprotection, diabetes and fertility. However, it seems now consensual that toxicity concerns related to methylxanthine consumption and/or therapeutic use should not be dismissed. Taking all the knowledge and expectations on the potential of methylxanthines into account, we propose a systematic look at the past and future of methylxanthine pharmacol. applications, discussing all the promise and anticipating possible constraints. Anyways, methylxanthines will still substantiate considerable meaningful research and discussion for years to come.(b) Matera, M. G.; Page, C. P.; Calzetta, L.; Rogliani, P.; Cazzola, M. Pharmacology and therapeutics of bronchodilators revisited. Pharmacol. Rev. 2020, 72, 218– 252, DOI: 10.1124/pr.119.018150[Crossref], [PubMed], [CAS], Google Scholar34bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXitFGitbzF&md5=f60fcee4ec5622bddb815d2250523ec9Pharmacology and therapeutics of bronchodilators revisitedMatera, M. G.; Page, C. P.; Calzetta, L.; Rogliani, P.; Cazzola, M.Pharmacological Reviews (2020), 72 (1), 218-252CODEN: PAREAQ; ISSN:1521-0081. (American Society for Pharmacology and Experimental Therapeutics)Bronchodilators remain the cornerstone of the treatment of airway disorders such as asthma and chronic obstructive pulmonary disease (COPD). How to optimize the use of our existing classes of bronchodilator and in identifying novel classes of bronchodilator drugs. Recent research has shown that optimization of bronchodilation occurs when both arms of the autonomic nervous system are affected through antagonism of muscarinic receptors to reduce the influence of parasympathetic innervation of the lung and through stimulation of b2-adrenoceptors (b2-ARs) on airway smooth muscle with b2-AR-selective agonists to mimic the sympathetic influence on the lung. This is currently achieved by use of fixed-dose combinations of inhaled long-acting b2-adrenoceptor agonists (LABAs) and long-acting muscarinic acetylcholine receptor antagonists (LAMAs). Due to the distinct mechanisms of action of LAMAs and LABAs, the additive/synergistic effects of using these drug classes together has been extensively investigated. More recently, so-called "triple inhalers" contg. fixed-dose combinations of both classes of bronchodilator (dual bronchodilation) and an inhaled corticosteroid in the same inhaler have been developed. Furthermore, a no. of so-called "bifunctional drugs" having two different primary pharmacol. actions in the same mol. are under development. This review discusses recent advancements in knowledge on bronchodilators and bifunctional drugs for the treatment of asthma and COPD.
- 35(a) Shukla, D.; Chakraborty, S.; Singh, S.; Mishra, B. Doxofylline: a promising methylxanthine derivative for the treatment of asthma and chronic obstructive pulmonary disease. Expert Opin. Pharmacother. 2009, 10, 2343– 2356, DOI: 10.1517/14656560903200667[Crossref], [PubMed], [CAS], Google Scholar.35ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtFCgtLfK&md5=172dae88895bbac0ff31bd5e468ee4edDoxofylline: a promising methylxanthine derivative for the treatment of asthma and chronic obstructive pulmonary diseaseShukla, Dali; Chakraborty, Subhashis; Singh, Sanjay; Mishra, BrahmeshwarExpert Opinion on Pharmacotherapy (2009), 10 (14), 2343-2356CODEN: EOPHF7; ISSN:1465-6566. (Informa Healthcare)A review. Doxofylline, a methylxanthine deriv., has recently drawn attention because of its better safety profile and similar efficacy over the most widely prescribed analog, theophylline, indicated for asthma and chronic obstructive pulmonary disease. This article attempts to discuss the pharmacodynamics/pharmacokinetics and clin. efficacy of doxofylline. An extensive search in three electronic databases (Unbound Medline, Pubmed and Sciencedirect) and internet search engines (Scirus and Google Scholar) were used to identify the clin. studies on doxofylline. The literature search was carried out without time constraints to ensure max. coverage of existing literature on doxofylline. In a relatively large no. of comparative studies, doxofylline is indicated to have less affinity for α1 and α2 receptors than theophylline. Unlike theophylline, doxofylline does not antagonize calcium channels, nor does it interfere with the influx of calcium into the cells, which probably reduces the cardiac side effects. Moreover, it does not affect sleep rhythm, gastric secretions, heart rate and rhythm and CNS functioning. Numerous reports available regarding the better tolerability of doxofylline than theophylline prove it as a potential bronchodilator with promising pharmacol. behavior. However, despite its superior safety and clin. efficacy, the potential of doxofylline has not been fully exploited.(b) Matera, M. G.; Page, C.; Cazzola, M. Doxofylline is not just another theophylline!. Int. J. Chronic Obstruct. Pulm. Dis. 2017, 12, 3487– 3493, DOI: 10.2147/COPD.S150887[Crossref], [PubMed], [CAS], Google Scholar35bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXntVKnsb4%253D&md5=5d94dfedf43b6ebab35b7858f12984e8Doxofylline is not just another theophylline!Matera, Maria Gabriella; Page, Clive; Cazzola, MarioInternational Journal of Chronic Obstructive Pulmonary Disease (2017), 12 (), 3487-3493CODEN: IJCOC3; ISSN:1178-2005. (Dove Medical Press Ltd.)Doxofylline, which differs from theophylline in contg. the dioxalane group at position 7, has comparable efficacy to theophylline in the treatment of respiratory diseases, but with an improved tolerability profile and a favorable risk-to-benefit ratio. Furthermore, it does not have significant drug-drug interactions as exhibited with theophylline, which make using theophylline more challenging, esp. in elderly patients with co-morbidities receiving multiple classes of drug. It is now clear that doxofylline also possesses a distinct pharmacol. profile from theophylline (no significant effect on any of the known phosphodiesterase isoforms, no significant adenosine receptor antagonism, no direct effect on histone deacetylases, interaction with β2-adrenoceptors) and therefore, should not be considered as just a modified theophylline. Randomized clin. trials of doxofylline to investigate the use of this drug to reduce exacerbations and hospitalizations due to asthma or COPD as an alternative to expensive biologics, and certainly as an alternative to theophylline are to be encouraged.
- 36(a) Zhao, X.; Ma, H.; Pan, Q.; Wang, H.; Qian, X.; Song, P.; Zou, L.; Mao, M.; Xia, S.; Ge, G.; Yang, L. Theophylline acetaldehyde as the initial product in doxophylline metabolism in human liver. Drug Metab. Dispos. 2020, 48, 345– 352, DOI: 10.1124/dmd.119.089565[Crossref], [PubMed], [CAS], Google Scholar.36ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtVeqsbzO&md5=9464366706ab683a792e0ee28e56be05Theophylline acetaldehyde as the initial product in doxophylline metabolism in human liverZhao, Xiaohua; Ma, Hong; Pan, Qiusha; Wang, Haiyi; Qian, Xingkai; Song, Peifang; Zou, Liwei; Mao, Mingqing; Xia, Shuyue; Ge, Guangbo; Yang, LingDrug Metabolism & Disposition (2020), 48 (5), 345-352CODEN: DMDSAI; ISSN:1521-009X. (American Society for Pharmacology and Experimental Therapeutics)In this study, the metabolites of DOXO were characterized. A total of nine metabolites of DOXO were identified in vitro using liver microsomes from human and four other animal species. Among them, six metabolites were reported for the first time. The top three metabolites were theophylline acetaldehyde (M1), theophylline-7-acetic acid (M2), and etophylline (M4). A comparative anal. of DOXO metabolismin human using liver microsomes, S9 fraction, and plasma samples demonstrated the following: 1) The metab. of DOXO began with a cytochrome P 450 (P 450)-mediated, rate-limiting step at the C ring and produced M1, the most abundant metabolite in human liver microsomes. However, in human plasma, the M1 prodn. was rather low. 2) M1 was further converted to M2 and M4, the end products of DOXO metab. in vivo, by non-P 450 dismutase in the cytosol. This dismutation process also relied on the ratio of NADP+/NADPH in the cell. These findings for the first time elucidated the metabolic sites and routes of DOXO metab. in human. SIGNIFICANCE STATEMENT We systematically characterized doxophylline metab. using in vitro and in vivo assays. Our findings evolved the understandings of metabolic sites and pathways for methylxanthine derivs. with the aldehyde functional group.(b) Grosa, G.; Franzone, J. S.; Biglino, G. Metabolism of doxophylline by rat liver microsomes. Drug Metab. Dispos. 1986, 14, 267– 270[PubMed], [CAS], Google Scholar36bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL28XitFymtrY%253D&md5=18b758d2873af115bb42d57cd58f78caMetabolism of doxophylline by rat liver microsomesGrosa, G.; Franzone, J. S.; Biglino, G.Drug Metabolism and Disposition (1986), 14 (2), 267-70CODEN: DMDSAI; ISSN:0090-9556.The metabolic transformation of the bronchospasmolytic agent doxophylline (I) [69975-86-6] was studied in vitro with phenobarbital-induced rat liver microsomal fraction contg. the NADPH-generating system. Doxophylline was poorly metabolized as 95% of the recovered material was parent compd. The major metabolite was 2'-hydroxyethyl ester of theophylline acetic acid [61379-38-2]. Theophylline [58-55-9] was a minor metabolite. The per cent ratio of the two metabolites was 4:1. Doxophylline appears to undergo a regiospecific metab. on the N7 side chain.
- 37Griebel, G.; Stemmelin, J.; Lopez-Grancha, M.; Fauchey, V.; Slowinski, F.; Pichat, P.; Dargazanli, G.; Abouabdellah, A.; Cohen, C.; Bergis, O. E. The selective reversible FAAH inhibitor, SSR411298, restores the development of maladaptive behaviors to acute and chronic stress in rodents. Sci. Rep. 2018, 8, 2416, DOI: 10.1038/s41598-018-20895-z[Crossref], [PubMed], [CAS], Google Scholar37https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1MvnsF2mtQ%253D%253D&md5=924080603c7791f41ef83e9d8890fcb5The selective reversible FAAH inhibitor, SSR411298, restores the development of maladaptive behaviors to acute and chronic stress in rodentsGriebel Guy; Stemmelin Jeanne; Lopez-Grancha Mati; Fauchey Valerie; Slowinski Franck; Dargazanli Gihad; Abouabdellah Ahmed; Pichat Philippe; Cohen Caroline; Bergis Olivier EScientific reports (2018), 8 (1), 2416 ISSN:.Enhancing endogenous cannabinoid (eCB) signaling has been considered as a potential strategy for the treatment of stress-related conditions. Fatty acid amide hydrolase (FAAH) represents the primary degradation enzyme of the eCB anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). This study describes a potent reversible FAAH inhibitor, SSR411298. The drug acts as a selective inhibitor of FAAH, which potently increases hippocampal levels of AEA, OEA and PEA in mice. Despite elevating eCB levels, SSR411298 did not mimic the interoceptive state or produce the behavioral side-effects (memory deficit and motor impairment) evoked by direct-acting cannabinoids. When SSR411298 was tested in models of anxiety, it only exerted clear anxiolytic-like effects under highly aversive conditions following exposure to a traumatic event, such as in the mouse defense test battery and social defeat procedure. Results from experiments in models of depression showed that SSR411298 produced robust antidepressant-like activity in the rat forced-swimming test and in the mouse chronic mild stress model, restoring notably the development of inadequate coping responses to chronic stress. This preclinical profile positions SSR411298 as a promising drug candidate to treat diseases such as post-traumatic stress disorder, which involves the development of maladaptive behaviors.
- 38Garde, D. J&J halts a depression program in the shadow of a fatal French trial. https://www.fiercebiotech.com/r-d/j-j-halts-a-depression-program-shadow-of-a-fatal-french-trial (accessed March 17, 2021).
- 39Belema, M.; Meanwell, N. A. Discovery of daclatasvir, a pan-genotypic hepatitis C virus NS5A replication complex inhibitor with potent clinical effect. J. Med. Chem. 2014, 57, 5057– 5071, DOI: 10.1021/jm500335h[ACS Full Text], [CAS], Google Scholar39https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXmsFWgurs%253D&md5=1428746b49ba356ce6993a58b143e5dcDiscovery of Daclatasvir, a Pan-Genotypic Hepatitis C Virus NS5A Replication Complex Inhibitor with Potent Clinical EffectBelema, Makonen; Meanwell, Nicholas A.Journal of Medicinal Chemistry (2014), 57 (12), 5057-5071CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. The discovery and development of the first-in-class hepatitis C virus (HCV) NS5A replication complex inhibitor daclatasvir provides a compelling example of the power of phenotypic screening to identify leads engaging novel targets in mechanistically unique ways. HCV NS5A replication complex inhibitors are pan-genotypic in spectrum, and this mechanistic class provides the most potent HCV inhibitors in vitro that have been described to date. Clin. trials with daclatasvir demonstrated a potent effect on reducing plasma viral load and, in combination with mechanistically orthogonal HCV inhibitors, established the ability to cure even the most difficult infections without the need for immune stimulation. In this Drug Annotation, the authors describe the discovery of the original high-throughput screening lead BMS-858 and the chem. conundrum and challenges resolved in optimizing to daclatasvir as a clin. candidate and finally the authors summarize the results of select clin. studies.
- 40(a) Kazmierski, W. W.; Maynard, A.; Duan, M.; Baskaran, S.; Botyanszki, J.; Crosby, R.; Dickerson, S.; Tallant, M.; Grimes, R.; Hamatake, R.; Leivers, M.; Roberts, C. D.; Walker, J. Novel spiroketal pyrrolidine GSK2336805 potently inhibits key hepatitis C virus genotype 1b mutants: from lead to clinical compound. J. Med. Chem. 2014, 57, 2058– 2073, DOI: 10.1021/jm4013104[ACS Full Text.], [CAS], Google Scholar40ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXjt1ynurw%253D&md5=630673e83d4360ea66b420287feb5451Novel Spiroketal Pyrrolidine GSK2336805 Potently Inhibits Key Hepatitis C Virus Genotype 1b Mutants: From Lead to Clinical CompoundKazmierski, Wieslaw M.; Maynard, Andrew; Duan, Maosheng; Baskaran, Sam; Botyanszki, Janos; Crosby, Renae; Dickerson, Scott; Tallant, Matthew; Grimes, Rick; Hamatake, Robert; Leivers, Martin; Roberts, Christopher D.; Walker, JillJournal of Medicinal Chemistry (2014), 57 (5), 2058-2073CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Rapid clin. progress of hepatitis C virus (HCV) replication inhibitors, including these selecting for resistance in the NS5A region (NS5A inhibitors), promises to revolutionize HCV treatment. Herein, we describe our explorations of diverse spiropyrrolidine motifs in novel NS5A inhibitors and a proposed interaction model. We discovered that the 1,4-dioxa-7-azaspiro[4.4]nonane motif in inhibitor 41H (I, GSK2236805) supported high potency against genotypes 1a and 1b as well as in genotype 1b L31V and Y93H mutants. Consistent with this, 41H potently suppressed HCV RNA in the 20-day RNA redn. assay. Pharmacokinetic and safety data supported further progression of 41H to the clinic.(b) Wilfret, D. A.; Walker, J.; Adkison, K. K.; Jones, L. A.; Lou, Y.; Gan, J.; Castellino, S.; Moseley, C. L.; Horton, J.; de Serres, M.; Culp, A.; Goljer, I.; Spreen, W. Safety, tolerability, pharmacokinetics, and antiviral activity of GSK2336805, an inhibitor of hepatitis C virus (HCV) NS5A, in healthy subjects and subjects chronically infected with HCV genotype 1. Antimicrob. Agents Chemother. 2013, 57, 5037– 5044, DOI: 10.1128/AAC.00910-13[Crossref], [PubMed], [CAS], Google Scholar40bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVygtLfN&md5=8e9f3eee73c0e688f1dae5510f3c1fc7Safety, tolerability, pharmacokinetics, and antiviral activity of GSK2336805, an inhibitor of hepatitis C virus (HCV) NS5A, in healthy subjects and subjects chronically infected with HCV genotype 1Wilfret, D. A.; Walker, J.; Adkison, K. K.; Jones, L. A.; Lou, Y.; Gan, J.; Castellino, S.; Moseley, C. L.; Horton, J.; de Serres, M.; Culp, A.; Goljer, I.; Spreen, W.Antimicrobial Agents and Chemotherapy (2013), 57 (10), 5037-5044CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)GSK2336805 is an orally bioavailable hepatitis C virus (HCV) inhibitor working through an NS5A-mediated mechanism. This first-time-in-human study was conducted to assess the safety, tolerability, pharmacokinetics, metab., and efficacy of GSK2336805 in healthy subjects and subjects infected with HCV genotype 1. We performed a three-part, randomized, double-blind, placebo-controlled study in 46 healthy subjects and 23 HCV-infected subjects. After an overnight fast, healthy subjects received GSK2336805 as 10 mg, 30 mg, 30 mg plus food, and 60 mg in a single dose and 10 mg (7 days), 30 mg (7 days), and 75 mg (14 days) in a once-daily multiple dose. Subjects with HCV received GSK2336805 as a 1- to 120-mg single dose. In subjects with HCV, redns. in HCV RNA were obsd. within 4 h and a single dose of GSK2336805 of ≥10 mg resulted in a statistically significant ≥2-log redn. in HCV RNA compared with placebo at 24 h postdose. GSK2336805 was readily absorbed in all subjects, and the half-life (t1/2) was suitable for once-daily dosing. Administration of GSK2336805 with food had no effect on plasma GSK2336805 exposure; however, absorption was delayed, with a median tmax (time to max. concn. of drug in serum) of 4.5 vs. 2.0 h. Twenty subjects who received GSK2336805 experienced mild to moderate adverse events; none were serious. GSK2336805 was well tolerated and exhibited rapid, significant antiviral activity after a single dose in HCV-infected subjects. These results support the conduct of further studies evaluating GSK2336805 administered once daily for longer durations in combination with peginterferon, ribavirin, and other direct-acting antivirals.
- 41Tai, V. W.; Garrido, D.; Price, D. J.; Maynard, A.; Pouliot, J. J.; Xiong, Z.; Seal III, J. W.; Creech, K. L.; Kryn, L. H.; Baughman, T. M.; Peat, A. J. Design and synthesis of spirocyclic compounds as HCV replication inhibitors by targeting viral NS4B protein. Bioorg. Med. Chem. Lett. 2014, 24, 2288– 2294, DOI: 10.1016/j.bmcl.2014.03.080[Crossref], [PubMed], [CAS], Google Scholar41https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXmt1Wlu7s%253D&md5=e221782d8c961d7b60348c98d3de0da1Design and synthesis of spirocyclic compounds as HCV replication inhibitors by targeting viral NS4B proteinTai, Vincent W.-F.; Garrido, Dulce; Price, Daniel J.; Maynard, Andrew; Pouliot, Jeffrey J.; Xiong, Zhiping; Seal, John W.; Creech, Katrina L.; Kryn, Luz H.; Baughman, Todd M.; Peat, Andrew J.Bioorganic & Medicinal Chemistry Letters (2014), 24 (10), 2288-2294CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Pyrazolo[1,5-a]pyridinecarbonyl-substituted spiropiperidines such as pyrazolo[1,5-a]pyridinecarbonyl dispirocyclopropanedioxanepiperidinol I and pyrazolo[1,5-a]pyridinecarbonyl hydroxyspiropiperidineoxazolidinone II were prepd. as inhibitors of hepatitis C viral protein NS4B; their inhibition of HCV replicons 1a and 1b and their lack of cytotoxicity in human cells at concns. < 25 μM were detd. Spirocyclic piperidine ketals such as I were prepd. which showed in vitro anti-HCV activities; for example, I showed EC50 of 1.5 nM and 1.2 nM against genotype 1a and 1b replicons, resp., in vitro. Spirocyclic piperidine oxazolidinones such as II were prepd.; II showed EC50 values of 10.9 nM and 6.1 nM against HCV 1a and 1b replicons, resp. The solubilities, permeabilities in the presence of P-gp transporters, half-life, and calcd. lipophilicities, polar surface areas, and lipophilic ligand efficiencies were detd. for selected compds. including I and II. Both I and II bound directly to non-structural NS4B protein in vitro (IC50 values of 10.2 nM and 30.4 nM, resp.); I and II exhibited reduced potency (27-185-fold increases in EC50 values) in replicons contg. resistance mutations encoding changes (H94N and V105M) in the NS4B protein. The structure of a dispirocyclopropanedioxanepiperidine di-O-p-toluoyltartrate salt used in the prepn. of I was detd. by X-ray crystallog.
- 42(a) Chen, K. X.; Njoroge, G.; Arasappan, A.; Venkatraman, S.; Vibulbhan, B.; Yang, W.; Parekh, T. N.; Pichardo, J.; Prongay, A.; Cheng, K.; Butkiewicz, N.; Yao, N.; Madison, V.; Girijavallabhan, V. Novel potent hepatitis C virus NS3 serine protease inhibitors derived from proline-based macrocycles. J. Med. Chem. 2006, 49, 995– 1005, DOI: 10.1021/jm050820s[ACS Full Text.], [CAS], Google Scholar42ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XitV2mtQ%253D%253D&md5=113c44a06c8018697ee83ae8614b6a95Novel Potent Hepatitis C Virus NS3 Serine Protease Inhibitors Derived from Proline-Based MacrocyclesChen, Kevin X.; Njoroge, F. George; Arasappan, Ashok; Venkatraman, Srikanth; Vibulbhan, Bancha; Yang, Weiying; Parekh, Tejal N.; Pichardo, John; Prongay, Andrew; Cheng, Kuo-Chi; Butkiewicz, Nancy; Yao, Nanhua; Madison, Vincent; Girijavallabhan, ViyyoorJournal of Medicinal Chemistry (2006), 49 (3), 995-1005CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The hepatitis C virus (HCV) NS3 protease is essential for viral replication. It has been a target of choice for intensive drug discovery research. On the basis of an active pentapeptide inhibitor, I, we envisioned that macrocyclization from the P2 proline to P3 capping could enhance binding to the backbone Ala156 residue and the S4 pocket. Thus, a no. of P2 proline-based macrocyclic α-ketoamide inhibitors were prepd. and investigated in an HCV NS3 serine protease continuous assay (Ki*). The biol. activity varied substantially depending on factors such as the ring size, no. of amino acid residues, no. of Me substituents, type of heteroatom in the linker, P3 residue, and configuration at the proline C-4 center. The pentapeptide inhibitors were very potent, with the C-terminal acids and amides being the most active ones [II; R = H, R1 = cyclohexyl, R2 = NH-Gly-Phg-NMe2 (24), Ki* = 8 nM]. The tetrapeptides and tripeptides were less potent. Sixteen- and seventeen-membered macrocyclic compds. were equally potent, while fifteen-membered analogs were slightly less active. Gem-Di-Me substituents at the linker improved the potency of all inhibitors [the best compd. was II (R = Me, R1 = cyclohexyl, R2 = NH-Gly-Phg-NMe2) (45), Ki* = 6 nM]. The combination of tert-leucine at P3 and di-Me substituents at the linker in compd. II (R = Me, R1 = t-Bu, R2 = NH-Gly-Phg-NMe2) realized a selectivity of 307 against human neutrophil elastase. Compd. 45 had an IC50 of 130 nM in a cellular replicon assay, while IC50 for 24 was 400 nM. Several compds. had excellent s.c. AUC and bioavailability in rats. Although tripeptide compd. II (R = Me, R1 = cyclohexyl, R2 = NH-allyl) was 97% orally bioavailable, larger pentapeptides generally had low oral bioavailability. The X-ray crystal structure of compds. 24 and 45 bound to the protease demonstrated the close interaction of the macrocycle with the Ala156 Me group and S4 pocket. The strategy of macrocyclization has been proved to be successful in improving potency (>20-fold greater than that of I) and in structural depeptization.(b) Chen, K. X.; Njoroge, F. G.; Vibulbhan, B.; Prongay, A.; Pichardo, J.; Madison, V.; Buevich, A.; Chan, T. M. Proline-based macrocyclic inhibitors of the hepatitis C virus: stereoselective synthesis and biological activity. Angew. Chem., Int. Ed. 2005, 44, 7024– 7028, DOI: 10.1002/anie.200501553[Crossref], [CAS], Google Scholar42bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXht1KrsrjJ&md5=95822f091507b7daae129462cc641611Proline-based macrocyclic inhibitors of the hepatitis C virus: Stereoselective synthesis and biological activityChen, Kevin X.; Njoroge, F. George; Vibulbhan, Bancha; Prongay, Andrew; Pichardo, John; Madison, Vincent; Buevich, Alexei; Chan, Tze-MingAngewandte Chemie, International Edition (2005), 44 (43), 7024-7028CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)Macrocyclization through a Mitsunobu reaction was used to synthesize a 17-membered macrocycle. The bicyclic acetal core was prepd. completely diastereoselectively. For example, macrocycles I (R = OBu-t, OH, NMe2) were prepd. The macrocyclic peptidomimetic surrogate of the P2-P3 dipeptide moiety was designed to function as a hepatitis C virus (HCV) NS3 serine protease inhibitor, and the pentapeptide α-ketoamides derived from the macrocycle were shown to be potent HCV inhibitors.
- 43(a) Sanglier, J.-J.; Quesniaux, V.; Fehr, T.; Hofmann, H.; Mahnke, M.; Memmert, K.; Schuler, W.; Zenke, G.; Gschwind, L.; Maurer, C.; Schilling, W. Sanglifehrins A, B, C and D, novel cyclophilin-binding compounds isolated from Streptomyces sp. A92–308110: I. Taxonomy, fermentation, isolation and biological activity. J. Antibiot. 1999, 52, 466– 473, DOI: 10.7164/antibiotics.52.466[Crossref], [PubMed], [CAS], Google Scholar.43ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXjs1yhsbc%253D&md5=a8627873fed55ee57f2aa8ecd1cf58eeSanglifehrins A, B, C and D, novel cyclophilin-binding compounds isolated from Streptomyces sp. A92-308110: I. Taxonomy, fermentation, isolation and biological activitySanglier, Jean-Jacques; Quesniaux, Valerie; Fehr, Theodor; Hofmann, Hans; Mahnke, Marion; Memmert, Klaus; Schuler, Walter; Zenke, Gerhard; Gschwind, Liliane; Maurer, Claudine; Schilling, WolfgangJournal of Antibiotics (1999), 52 (5), 466-473CODEN: JANTAJ; ISSN:0021-8820. (Japan Antibiotics Research Association)A novel class of macrolides for which the name sanglifehrins is proposed has been discovered from actinomycete strains based on their high affinity binding for cyclophilin A (CypA), an immunophilin originally identified as a cytosolic protein binding cyclosporin A (CsA). The sanglifehrins were produced by Streptomyces sp. A92-308110. They were isolated and purified by extn. and several chromatog. activity-guided steps. Sanglifehrins A and B (I and II, resp., where R=A) exhibit a 10∼20 fold higher affinity for CypA than CsA, whereas the affinity of sanglifehrins C and D (III and IV, resp., where R=B) for CypA is comparable to that of CsA. Sanglifehrins exhibit a lower immunosuppressive activity than CsA when tested in the mixed lymphocyte reaction. Their in vitro activity indicates that they belong to a novel class of immunosuppressants.(b) Fehr, T.; Kallen, J.; Oberer, L.; Sanglier, J.-J.; Schilling, W. Sanglifehrins A, B, C and D, novel cyclophilin-binding compounds isolated from Streptomyces sp. A92–308110: II. Structure elucidation, stereochemistry and physico-chemical properties. J. Antibiot. 1999, 52, 474– 479, DOI: 10.7164/antibiotics.52.474[Crossref], [PubMed], [CAS], Google Scholar43bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXjs1yhtr4%253D&md5=36f9eb7ae761ad51a5a62bdccd1c4864Sanglifehrins A, B, C and D, novel cyclophilin-binding compounds isolated from Streptomyces sp. A92-308110: II. Structure elucidation, stereochemistry and physico-chemical propertiesFehr, Theodor; Kallen, Jorg; Oberer, Lukas; Sanglier, Jean-Jacques; Schilling, WolfgangJournal of Antibiotics (1999), 52 (5), 474-479CODEN: JANTAJ; ISSN:0021-8820. (Japan Antibiotics Research Association)A novel class of macrolides, the sanglifehrins, was discovered by screening of actinomycete strains with a cyclophilin-binding assay. The chem. structures and abs. stereochemistries of the sanglifehrins A, B, C and D were detd. unambiguously by NMR-techniques and by X-ray crystallog. of the complex with cyclophilin A. Sanglifehrin A consists of a 22-membered macrocycle contg. a tripeptide subunit and features in position 23 a chain of nine carbon atoms bearing a spirocyclic substituent. Sanglifehrins A and B are genuine metabolites whereas sanglifehrins C and D are artifacts.
- 44Mackman, R.; Steadman, V. A.; Dean, D. K.; Jansa, P.; Poullennec, K. G.; Appleby, T.; Austin, C.; Blakemore, C. A.; Cai, R.; Cannizzaro, C.; Chin, G.; Chiva, J. C.; Dunbar, N. A.; Fliri, H.; Highton, A. J.; Hui, H.; Ji, M.; Jin, H.; Karki, K.; Keats, A. J.; Lazarides, L.; Lee, Y.; Liclican, A.; Mish, M.; Murray, B.; Pettit, S. B.; Yun, P.; Sangi, M.; Santos, R.; Sanvoisin, J.; Schmitz, U.; Schrier, A.; Siegel, D.; Sperandio, D.; Stepan, G.; Tian, Y.; Watt, G. M.; Yang, H.; Schultz, B. E. Discovery of a potent and orally bioavailable cyclophilin inhibitor derived from the sanglifehrin macrocycle. J. Med. Chem. 2018, 61, 9473– 9499, DOI: 10.1021/acs.jmedchem.8b00802[ACS Full Text], [CAS], Google Scholar44https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsVChtbrI&md5=616cf72e0d2766e159769166c98a9e86Discovery of a potent and orally bioavailable cyclophilin inhibitor derived from the sanglifehrin macrocycleMackman, Richard L.; Steadman, Victoria A.; Dean, David K.; Jansa, Petr; Poullennec, Karine G.; Appleby, Todd; Austin, Carol; Blakemore, Caroline A.; Cai, Ruby; Cannizzaro, Carina; Chin, Gregory; Chiva, Jean-Yves C.; Dunbar, Neil A.; Fliri, Hans; Highton, Adrian J.; Hui, Hon; Ji, Mingzhe; Jin, Haolun; Karki, Kapil; Keats, Andrew J.; Lazarides, Linos; Lee, Yu-Jen; Liclican, Albert; Mish, Michael; Murray, Bernard; Pettit, Simon B.; Pyun, Peter; Sangi, Michael; Santos, Rex; Sanvoisin, Jonathan; Schmitz, Uli; Schrier, Adam; Siegel, Dustin; Sperandio, David; Stepan, George; Tian, Yang; Watt, Gregory M.; Yang, Hai; Schultz, Brian E.Journal of Medicinal Chemistry (2018), 61 (21), 9473-9499CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Cyclophilins are a family of peptidyl-prolyl isomerases that are implicated in a wide range of diseases including hepatitis C. Our aim was to discover through total synthesis an orally bioavailable, non-immunosuppressive cyclophilin (Cyp) inhibitor with potent anti-hepatitis C virus (HCV) activity that could serve as part of an all oral antiviral combination therapy. An initial lead (I) derived from the sanglifehrin A macrocycle was optimized using structure based design to produce a potent and orally bioavailable inhibitor (II). The macrocycle ring size was reduced by one atom, and an internal hydrogen bond drove improved permeability and drug-like properties. II demonstrates potent Cyp inhibition (Kd = 5 nM), potent anti-HCV 2a activity (EC50 = 98 nM), and high oral bioavailability in rat (100%) and dog (55%). The synthetic accessibility and properties of II support its potential as an anti-HCV agent and for interrogating the role of Cyp inhibition in a variety of diseases.
- 45Ma, X.; Idle, J. R.; Gonzalez, F. J. The pregnane X receptor: from bench to bedside. Expert Opin. Drug Metab. Toxicol. 2008, 4, 895– 908, DOI: 10.1517/17425255.4.7.895[Crossref], [PubMed], [CAS], Google Scholar45https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXos1Chur0%253D&md5=d485d79dfef46f99ab106007ab32993aThe pregnane X receptor: from bench to bedsideMa, Xiaochao; Idle, Jeffrey R.; Gonzalez, Frank J.Expert Opinion on Drug Metabolism & Toxicology (2008), 4 (7), 895-908CODEN: EODMAP; ISSN:1742-5255. (Informa Healthcare)A review. The pregnane X receptor (PXR; NR1I2), a member of the nuclear receptor superfamily, regulates the expression of metabolic enzymes and transporters involved in the response of mammals to their chem. environment. To summarize the functions and clin. implications of PXR. In the current review, the clin. implications of PXR are discussed, and the use of genetically engineered PXR mouse models is highlighted. Recent advances in mouse models, including Pxr-null and PXR-humanized mice, provide in vivo tools for evaluating the physiol. functions of PXR and its role in controlling xenobiotic metab. and transport. By using the PXR knockout and humanized mouse models, PXR was found to influence drug-drug interactions, hepatic steatosis, and the homeostasis of vitamin D, bile acids, and steroid hormones. PXR was also shown to influence inflammatory bowel diseases.
- 46Wang, Y.; Zhao, H.; Brewer, J. T.; Li, H.; Lao, Y.; Amberg, W.; Behl, B.; Akritopoulou-Zanze, I.; Dietrich, J.; Lange, U. E.; Pohlki, F.; Hoft, C.; Hornberger, W.; Djuric, S. W.; Sydor, J.; Mezler, M.; Relo, A. L.; Vasudevan, A. De novo design, synthesis, and biological evaluation of 3,4-disubstituted pyrrolidine sulfonamides as potent and selective glycine transporter 1 competitive inhibitors. J. Med. Chem. 2018, 61, 7486– 7502, DOI: 10.1021/acs.jmedchem.8b00295[ACS Full Text], [CAS], Google Scholar46https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXht1Cqu7jN&md5=8ccceff336374f790949111b56737d3cDe Novo Design, Synthesis, and Biological Evaluation of 3,4-Disubstituted Pyrrolidine Sulfonamides as Potent and Selective Glycine Transporter 1 Competitive InhibitorsWang, Ying; Zhao, Hongyu; Brewer, Jason T.; Li, Huanqiu; Lao, Yanbin; Amberg, Willi; Behl, Berthold; Akritopoulou-Zanze, Irini; Dietrich, Justin; Lange, Udo E. W.; Pohlki, Frauke; Hoft, Carolin; Hornberger, Wilfried; Djuric, Stevan W.; Sydor, Jens; Mezler, Mario; Relo, Ana Lucia; Vasudevan, AnilJournal of Medicinal Chemistry (2018), 61 (17), 7486-7502CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The development of glycine transporter 1 (GlyT1) inhibitors may offer putative treatments for schizophrenia and other disorders assocd. with hypofunction of the glutaminergic N-methyl-D-aspartate (NMDA) receptor. Herein, we describe the synthesis and biol. evaluation of a series of 3,4-disubstituted pyrrolidine sulfonamides as competitive GlyT1 inhibitors that arose from de novo scaffold design. Relationship of chem. structure to drug-drug interaction (DDI) and bioactivation was mechanistically investigated. Murine studies were strategically incorporated into the screening funnel to provide early assessments of in vivo target occupancy (TO) by ex vivo binding studies. Advanced compds. derived from iterative structure-activity relationship (SAR) studies possessed high potency in ex vivo binding studies and good brain penetration, promising preliminary in vivo efficacy, acceptable preclin. pharmacokinetics, and manageable DDI and bioactivation liabilities.
- 47(a) Lovering, F.; Bikker, J.; Humblet, C. Escape from flatland: increasing saturation as an approach to improving clinical success. J. Med. Chem. 2009, 52, 6752– 6756, DOI: 10.1021/jm901241e[ACS Full Text.], [CAS], Google Scholar47ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXht1KjtLvN&md5=4ca92c30c17c53d77ad376719bad951eEscape from Flatland: Increasing Saturation as an Approach to Improving Clinical SuccessLovering, Frank; Bikker, Jack; Humblet, ChristineJournal of Medicinal Chemistry (2009), 52 (21), 6752-6756CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The medicinal chem. community has become increasingly aware of the value of tracking calcd. phys. properties such as mol. wt., topol. polar surface area, rotatable bonds, and hydrogen bond donors and acceptors. The authors hypothesized that the shift to high-throughput synthetic practices over the past decade may be another factor that may predispose mols. to fail by steering discovery efforts toward achiral, arom. compds. The authors have proposed two simple and interpretable measures of the complexity of mols. prepd. as potential drug candidates. The first is carbon bond satn. as defined by fraction Sp3 (Fsp3) where Fsp3 = (no. of Sp3 hybridized carbons/total carbon count). The second is simply whether a chiral carbon exists in the mol. The authors demonstrate that both complexity (as measured by Fsp3) and the presence of chiral centers correlate with success as compds. transition from discovery, through clin. testing, to drugs. To explain these observations, the authors further demonstrate that satn. correlates with soly., an exptl. phys. property important to success in the drug discovery setting.(b) Hirata, K.; Kotoku, M.; Seki, N.; Maeba, T.; Maeda, K.; Hirashima, S.; Sakai, T.; Obika, S.; Hori, A.; Hase, Y.; Yamaguchi, T.; Katsuda, Y.; Hata, T.; Miyagawa, N.; Arita, K.; Nomura, Y.; Asahina, K.; Aratsu, Y.; Kamada, M.; Adachi, T.; Noguchi, M.; Doi, S.; Crowe, P.; Bradley, E.; Steensma, R.; Tao, H.; Fenn, M.; Babine, R.; Li, X.; Thacher, S.; Hashimoto, H.; Shiozaki, M. SAR Exploration guided by LE and Fsp3: discovery of a selective and orally efficacious RORδ inhibitor. ACS Med. Chem. Lett. 2016, 7, 23– 27, DOI: 10.1021/acsmedchemlett.5b00253[ACS Full Text], [CAS], Google Scholar47bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhslKlt77P&md5=fc2736f8baafee2084bb3adce7bb1a2eSAR Exploration Guided by LE and Fsp3: Discovery of a Selective and Orally Efficacious RORγ InhibitorHirata, Kazuyuki; Kotoku, Masayuki; Seki, Noriyoshi; Maeba, Takaki; Maeda, Katsuya; Hirashima, Shintaro; Sakai, Takayuki; Obika, Shingo; Hori, Akimi; Hase, Yasunori; Yamaguchi, Takayuki; Katsuda, Yoshiaki; Hata, Takahiro; Miyagawa, Naoki; Arita, Kojo; Nomura, Yukihiro; Asahina, Kota; Aratsu, Yusuke; Kamada, Masafumi; Adachi, Tsuyoshi; Noguchi, Masato; Doi, Satoki; Crowe, Paul; Bradley, Erin; Steensma, Ruo; Tao, Haiyan; Fenn, Morgan; Babine, Robert; Li, Xiaolin; Thacher, Scott; Hashimoto, Hiromasa; Shiozaki, MakotoACS Medicinal Chemistry Letters (2016), 7 (1), 23-27CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)A novel series of RORγ inhibitors was identified starting with the HTS hit compd. 2-(5-(2,3-dihydro-1H-inden-2-yl)-4-ethyl-4-H-1,2,4-triazol-3-ylthio)-N-(naphthalen-1-yl)acetamide. After SAR investigation based on a prospective consideration of two drug-likeness metrics, ligand efficiency (LE) and fraction of Sp3 carbon atoms (Fsp3), significant improvement of metabolic stability as well as redn. of CYP inhibition was obsd., which finally led to discovery of a selective and orally efficacious RORγ inhibitor (3R,4R)-1-acetyl-4-(4-cyclopropyl-5-(cis-3-isobutylcyclobutyl)-4H-1,2,4-triazol-3-yl)-M-(2,4-dimethylphenyl) pyrrolidine-3-carboxamide.
- 48Stojanovic-Radic, Z.; Pejic, M.; Dimitrijevic, M.; Aleksic, A.; Kumar, N. V.; Salehi, B.; Cho, W. C.; Sharifi-Rad, J. Piperine - a major principle of black pepper: a review of its bioactivity and studies. Appl. Sci. 2019, 9, 4270, DOI: 10.3390/app9204270[Crossref], [CAS], Google Scholar48https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXntlKiurg%253D&md5=6f319b1ffffa93cbe7f680b2323763e4Piperine-A major principle of black pepper: a review of its bioactivity and studiesStojanovic-Radic, Zorica; Pejcic, Milica; Dimitrijevic, Marina; Aleksic, Ana; Kumar, Nanjangud V. Anil; Salehi, Bahare; Cho, William C.; Sharifi-Rad, JavadApplied Sciences (2019), 9 (20), 4270CODEN: ASPCC7; ISSN:2076-3417. (MDPI AG)Piperine is the main compd. present in black pepper, and is the carrier of its specific pungent taste, which is responsible for centuries of human dietary utilization and worldwide popularity as a food ingredient. Along with the application as a food ingredient and food preservative, it is used in traditional medicine for many purposes, which has in most cases been justified by modern scientific studies on its biol. effects. It has been confirmed that piperine has many bioactive effects, such as antimicrobial action, as well as many physiol. effects that can contribute to general human health, including immunomodulatory, hepatoprotective, antioxidant, antimetastatic, antitumor, and many other activities. Clin. studies demonstrated remarkable antioxidant, antitumor, and drug availability-enhancing characteristics of this compd., together with immunomodulatory potential. All these facts point to the therapeutic potential of piperine and the need to incorporate this compd. into general health-enhancing medical formulations, as well as into those that would be used as adjunctive therapy in order to enhance the bioavailability of various (chemo)therapeutic drugs.
- 49(a) Bertelsen, K. M.; Venkatakrishnan, K.; von Moltke, L. L.; Obach, R. S.; Greenblatt, D. J. Apparent mechanism-based inhibition of human CYP 2D6 in vitro by paroxetine: comparison with fluoxetine and quinidine. Drug Metab. Dispos. 2003, 31, 289– 293, DOI: 10.1124/dmd.31.3.289[Crossref], [PubMed], [CAS], Google Scholar.49ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXhsFKlt7Y%253D&md5=2336fbc058e49e7b530562809c62ba09Apparent mechanism-based inhibition of human CYP2D6 in vitro by paroxetine: Comparison with fluoxetine and quinidineBertelsen, Kirk M.; Venkatakrishnan, Karthik; Von Moltke, Lisa L.; Obach, R. Scott; Greenblatt, David J.Drug Metabolism and Disposition (2003), 31 (3), 289-293CODEN: DMDSAI; ISSN:0090-9556. (American Society for Pharmacology and Experimental Therapeutics)Paroxetine, a selective serotonin reuptake inhibitor, is a potent inhibitor of cytochrome P 450 2D6 (CYP2D6) activity, but the mechanism of inhibition is not established. To det. whether preincubation affects the inhibition of human liver microsomal dextromethorphan demethylation activity by paroxetine, we used a two-step incubation scheme in which all of the enzyme assay components, minus substrate, are preincubated with paroxetine. The kinetic parameters of inhibition were also estd. by varying the time of preincubation as well as the concn. of inhibitor. From these data, a Kitz-Wilson plot was constructed, allowing the estn. of both an apparent inactivator concn. required for half-maximal inactivation (KI) and the maximal rate const. of inactivation (KINACT) value for this interaction. Preincubation of paroxetine with human liver microsomes caused an approx. 8-fold redn. in the IC50 value (0.34 vs. 2.54 μM). Time-dependent inhibition was demonstrated with an apparent KI of 4.85 μM and an apparent KINACT value of 0.17 min-1. Spectral scanning of CYP2D6 with paroxetine yielded an increase in absorbance at 456 nm suggesting paroxetine inactivation of CYP2D6 via the formation of a metabolite intermediate complex. This pattern is consistent with the metab. of the methylenedioxy substituent in paroxetine; such substituents may produce mechanism-based inactivation of cytochrome P 450 enzymes. In contrast, quinidine and fluoxetine, both of which are inhibitors of CYP2D6 activity, did not exhibit a preincubation-dependent increase in inhibitory potency. These data are consistent with mechanism-based inhibition of CYP2D6 by paroxetine but not by quinidine or fluoxetine.(b) Kamel, E. M.; Lamsabhi, A. M. The quasi-irreversible inactivation of Cytochrome P450 enzymes by paroxetine: A computational approach. Org. Biomol. Chem. 2020, 18, 3334– 3345, DOI: 10.1039/D0OB00529K[Crossref], [PubMed], [CAS], Google Scholar.49bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXmsV2rsbY%253D&md5=8fea1e5717b3d39f5ef42aeb344af8afThe quasi-irreversible inactivation of cytochrome P450 enzymes by paroxetine: a computational approachKamel, Emadeldin M.; Lamsabhi, Al MokhtarOrganic & Biomolecular Chemistry (2020), 18 (17), 3334-3345CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)The mechanism-based inactivation (MBI) of P 450 by paroxetine was investigated by computational anal. The drug-enzyme interactions were figured out through studying energy profiles of three competing mechanisms. The potency of paroxetine as P 450's inhibitor was estd. based on the availability of two active sites for the MBI in the paroxetine structure. The inactivation by the amino site of paroxetine mainly proceeds via the hydrogen atom transfer pathway because of the lower energy demand of its rate detg. step. In addn., the low-spin state is the predominant route in the MBI at the methylenedioxo active site as a result of being rebound barrier-free mechanism. Our comparative investigation showed that inactivation at the secondary amine is thermodynamically more favorable because of the lower energy barrier of the dehydration mechanism of the hydroxylated paroxetine complex than its methylenedioxo counterpart. The results of docking anal. coincided with the outputs of DFT calcns. since the docking pose with the lowest binding affinity is that for conformation with polar interaction between the amino group of paroxetine and the oxo moiety of P 450's active site. Assessment of the mol. dynamics simulations trajectories revealed the favorable interaction of paroxetine with P 450.(c) Zhao, S. X.; Dalvie, D. K.; Kelly, J. M.; Soglia, J. R.; Frederick, K. S.; Smith, E. B.; Obach, R. S.; Kalgutkar, A. S. NADPH-dependent covalent binding of [3H]paroxetine to human liver microsomes and S-9 fractions: identification of an electrophilic quinone metabolite of paroxetine. Chem. Res. Toxicol. 2007, 20, 1649– 1657, DOI: 10.1021/tx700132x[ACS Full Text], [CAS], Google Scholar49chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtFSkurrK&md5=e7d3aa749a419cc87340271eb9b839a0NADPH-Dependent Covalent Binding of [3H]Paroxetine to Human Liver Microsomes and S-9 Fractions: Identification of an Electrophilic Quinone Metabolite of ParoxetineZhao, Sabrina X.; Dalvie, Deepak K.; Kelly, Joan M.; Soglia, John R.; Frederick, Kosea S.; Smith, Evan B.; Obach, R. Scott; Kalgutkar, Amit S.Chemical Research in Toxicology (2007), 20 (11), 1649-1657CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)The primary pathway of clearance of the methylenedioxyphenyl-contg. compd. and selective serotonin reuptake inhibitor paroxetine in humans involves P 450 2D6-mediated demethylenation to a catechol intermediate. The process of demethylenation also results in the mechanism-based inactivation of the P 450 isoenzyme. While the link between P 450 2D6 inactivation and pharmacokinetic interactions of paroxetine with P 450 2D6 substrates has been firmly established, there is a disconnect in terms of paroxetine's excellent safety record despite the potential for bioactivation. In the present study, the authors have systematically assessed the NADPH-dependent covalent binding of [3H]paroxetine to human liver microsomes and S-9 prepns. in the absence and presence of cofactors of the various phase II drug-metabolizing enzymes involved in the downstream metab./detoxification of the putative paroxetine-catechol intermediate. Incubation of [3H]paroxetine with human liver microsomes and S-9 prepns. resulted in irreversible binding of radioactive material to macromols. by a process that was NADPH-dependent. The addn. of reduced glutathione (GSH) to the microsomal and S-9 incubations resulted in a dramatic redn. of covalent binding. Following incubations with NADPH- and GSH-supplemented human liver microsomes and S-9, three sulfhydryl conjugates with MH+ ions at 623 Da (GS1), 779 Da (GS2), and 928 Da (GS3), resp., were detected by LC-MS/MS. The collision-induced dissocn. spectra allowed an insight into the structure of the GSH conjugates, based on which, bioactivation pathways were proposed. The formation of GS1 was consistent with Michael addn. of GSH to the quinone derived from two-electron oxidn. of paroxetine-catechol. GS3 was formed by the addn. of a second mol. of GSH to the quinone species obtained via the two-electron oxidn. of GS1. The mechanism of formation of GS2 can be rationalized via (i) further two-electron oxidn. of the catechol motif in GS3 to the ortho-quinone, (ii) loss of a glutamic acid residue from one of the adducted GSH mols., and (iii) condensation of a cysteine-NH2 with an adjacent carbonyl of the ortho-quinone to yield an ortho-benzoquinoneimine structure. Inclusion of the catechol-O-methyltransferase cofactor S-adenosylmethionine (SAM) in S-9 incubations also dramatically reduced the covalent binding of [3H]paroxetine, a finding that was consistent with O-methylation of the paroxetine-catechol metabolite to the corresponding guaiacol regioisomers in S-9 incubations. While the NADPH-dependent covalent binding was attenuated by GSH and SAM, these reagents did not alter paroxetine's ability to inactivate P 450 2D6, suggesting that the reactive intermediate responsible for P 450 inactivation did not leave the active site to react with other proteins. The results of the studies indicate that in addn. to the low once-a-day dosing regimen (20 mg) of paroxetine, efficient scavenging of the catechol and quinone metabolites by SAM and GSH, resp., serves as an explanation for the excellent safety record of paroxetine despite the fact that it undergoes bioactivation.
- 50(a) Daugan, A.; Grondin, P.; Ruault, C.; Le Monnier de Gouville, A.-C.; Coste, H.; Kirilovsky, J.; Hyafil, F.; Labaudiniere, R. The discovery of tadalafil: a novel and highly selective PDE5 Inhibitor. 1:5,6,11,11a-tetrahydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b]indole-1,3(2H)-dione analogues. J. Med. Chem. 2003, 46, 4525– 4532, DOI: 10.1021/jm030056e[ACS Full Text.], [CAS], Google Scholar50ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXnvVCju78%253D&md5=7c3b9aaf206cb18faaafc398c304357cThe discovery of tadalafil: a novel and highly selective PDE5 inhibitor. 1: 5,6,11,11a-tetrahydro-1H-imidazo[1',5':1,6]pyrido[3,4-b]indole-1,3(2H)-dione analoguesDaugan, Alain; Grondin, Pascal; Ruault, Cecile; Le Monnier de Gouville, Anne-Charlotte; Coste, Herve; Kirilovsky, Jorge; Hyafil, Francois; Labaudiniere, RichardJournal of Medicinal Chemistry (2003), 46 (21), 4525-4532CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Starting from Et β-carboline-3-carboxylate (β-CCE), 1, a modest inhibitor of type 5 phosphodiesterase (PDE5), a series of functionalized tetrahydro-β-carboline derivs. has been identified as a novel chem. class of potent and selective PDE5 inhibitors. Optimization of the side chain on the hydantoin ring of initial lead compd. 2 and of the arom. ring on position 5 led to the identification of compd. 6e, a highly potent and selective PDE5 inhibitor, with greater selectivity for PDE5 vs. PDE1-4 than sildenafil. Compd. 6e demonstrated a long lasting and significant blood pressure lowering effect after iv administration in the spontaneously hypertensive rat model but showed only moderate oral in vivo efficacy.(b) Daugan, A.; Grondin, P.; Ruault, C.; Le Monnier de Gouville, A. C.; Coste, H.; Linget, J. M.; Kirilovsky, J.; Hyafil, F.; Labaudinière, R. The discovery of tadalafil: a novel and highly selective PDE5 Inhibitor. 2:2,3,6,7,12,12a-hexahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione analogues. J. Med. Chem. 2003, 46, 4533– 4542, DOI: 10.1021/jm0300577[ACS Full Text.], [CAS], Google Scholar50bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXnvVCisrs%253D&md5=daaf79b5155dcea5b8c258fe7b05f436The discovery of tadalafil: a novel and highly selective PDE5 inhibitor. 2: 2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione analogueDaugan, Alain; Grondin, Pascal; Ruault, Cecile; Le Monnier de Gouville, Anne-Charlotte; Coste, Herve; Linget, Jean Michel; Kirilovsky, Jorge; Hyafil, Francois; Labaudiniere, RichardJournal of Medicinal Chemistry (2003), 46 (21), 4533-4542CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Modification of the hydantoin ring in the previously described lead compd. 2a has led to the discovery of compd. 12a, tadalafil, a highly potent and highly selective PDE5 inhibitor. The replacement of the hydantoin in compd. 2a by a piperazinedione ring led to compd. cis-11a which showed similar PDE5 inhibitory potency. Introduction of a 3,4-methylenedioxy substitution on the Ph ring in position 6 led to a potent PDE5 inhibitor cis-11c with increased cellular potency. Optimization of the chain on the piperazinedione ring led to the identification of the racemic cis-N-Me deriv. 11i. High diastereospecificity for PDE5 inhibition was obsd. in the piperazinedione series with the cis-(6R,12aR) enantiomer displaying the highest PDE5 inhibitory activity. The piperazinedione 12a, tadalafil (GF196960), has been identified as a highly potent PDE5 inhibitor (IC50 = 5 nM) with high selectivity for PDE5 vs. PDE1-4 and PDE6. Compd. 12a displays 85-fold greater selectivity vs. PDE6 than sildenafil 1. 12A showed profound and long-lasting blood pressure lowering activity (30 mmHg/>7 h) in the spontaneously hypertensive rat model after oral administration (5 mg/kg).(c) Curran, M. P.; Keating, G. M. Tadalafil. Drugs 2003, 63, 2203– 2212, DOI: 10.2165/00003495-200363200-00004[Crossref], [PubMed], [CAS], Google Scholar50chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXptFCis78%253D&md5=c749c366bbb1d7175bc4bb14ddd5cea5TadalafilCurran, Monique P.; Keating, Gillian M.Drugs (2003), 63 (20), 2203-2212CODEN: DRUGAY; ISSN:0012-6667. (Adis International Ltd.)A review. Tadalafil is a selective phosphodiesterase type 5 inhibitor that is effective in men with mild-to-severe erectile dysfunction (ED), including those with diabetes mellitus. The improvement in the erectile function domain score on the International Index of Erectile Function (IIEF) and the percentage of sexual intercourse attempts marked by successful vaginal penetration and completion was significantly greater with on-demand (not more than once daily) tadalafil 10 or 20mg than placebo in trials of 12 wk' duration. Improvement in scores on other domains of the IIEF and the percentage of pos. responses to a Global Assessment Question measuring erection improvement were also significantly greater with on-demand tadalafil than placebo. The adverse events assocd. with tadalafil were generally mild to moderate and decreased in frequency with continued administration. The most commonly reported adverse events were headache and dyspepsia. The incidence of cardiovascular adverse events was not significantly different in tadalafil or placebo recipients.
- 51Hartmann, J. T.; Lipp, H.-P. Camptothecin and podophyllotoxin derivatives inhibitors of topoisomerase I and II - mechanisms of action, pharmacokinetics and toxicity profile. Drug Saf. 2006, 29, 209– 230, DOI: 10.2165/00002018-200629030-00005[Crossref], [PubMed], [CAS], Google Scholar51https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XjslClsb8%253D&md5=96237fb19afbeb81954d01d06979733fCamptothecin and podophyllotoxin derivatives: inhibitors of topoisomerase I and II - mechanisms of action, pharmacokinetics and toxicity profileHartmann, Joerg T.; Lipp, Hans-PeterDrug Safety (2006), 29 (3), 209-230CODEN: DRSAEA; ISSN:0114-5916. (Adis International Ltd.)A review. Camptothecins represent an established class of effective agents that selectively target topoisomerase I by trapping the catalytic intermediate of the topoisomerase I-DNA reaction, the cleavage complex. The water-sol. salt camptothecin-sodium - introduced in early trials in the 1960s - was highly toxic in animals, whereas the semisynthetic derivs. irinotecan and topotecan did not cause hemorrhagic cystitis because of their higher physicochem. stability and soly. at lower pH values. Myelosuppression, neutropenia and, to a lesser extent, thrombocytopenia are dose-limiting toxic effects of topotecan. In contrast to the structurally-related topotecan, irinotecan is a prodrug which has to be converted to SN-38, its active form. SN-38 is inactivated by conjugation, thus patients with Gilbert's syndrome and other forms of genetic glucuronidation deficiency are at an increased risk of irinotecan-induced adverse effects, such as neutropenia and diarrhea. The cytotoxic mechanism of podophyllotoxin is the inhibition of topoisomerase II. Common adverse effects of etoposide include dose-limiting myelosuppression. Hypersensitivity reactions are more common with etoposide and teniposide than with etoposide phosphate because the formulations of the former contain sensitizing solubilizers. Leukopenia and thrombocytopenia occur in 65% and 80%, resp., of patients after administration of conventional doses of teniposide. Anorexia, vomiting and diarrhea are generally of mild severity after administration of conventional doses of topoisomerase II inhibitors. Clin. pharmacokinetic studies have revealed substantial interindividual variabilities regarding the area under the concn.-time curve values and steady-state concns. for all drugs reviewed in this article. Irinotecan, etoposide and teniposide are degraded via complex metabolic pathways. In contrast, topotecan primarily undergoes renal excretion. Regarding etoposide and teniposide, the extent of catechol formation over time during drug metab. may be assocd. with a higher risk for secondary malignancies.
- 52Murray, M. Mechanisms of inhibitory and regulatory effects of methylenedioxyphenyl compounds on cytochrome P450-dependent drug oxidation. Curr. Drug Metab. 2000, 1, 67– 84, DOI: 10.2174/1389200003339270[Crossref], [PubMed], [CAS], Google Scholar52https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXlt1Whurs%253D&md5=dcafc824c8bcd0080d256d6dd8c50ae7Mechanisms of inhibitory and regulatory effects of methylenedioxyphenyl compounds on cytochrome P450-dependent drug oxidationMurray, MichaelCurrent Drug Metabolism (2000), 1 (1), 67-84CODEN: CDMUBU ISSN:. (Bentham Science Publishers Ltd.)A review with 110 refs. Cytochrome P 450 (CYP) enzymes catalyze the oxidative conversion of drugs and other lipophilic compds. to hydrophilic metabolites. Thus, CYPs play a dominant role in the elimination of drugs from the body. Inhibitory interactions occur when drugs compete for oxidn. by specific CYPs, whereas certain drugs increase the capacity for oxidative biotransformation by inducing the synthesis of new CYPs. Methylenedioxyphenyl (MDP) compds. have been widely employed as com. important pesticide synergists and a no. of derivs. are found in oils and spices. MDP compds. are of considerable toxicol. significance because of their capacity to inhibit and induce CYP enzymes in mammals; some derivs. produce neurotoxic and hepatotoxic effects. Although there are relatively few therapeutic agents of present clin. importance that possess the MDP structural feature, the synthesis and preclin. evaluation of such agents appears to be increasing. In the context of the existing literature surrounding MDP compds. it is noteworthy that these potential drugs also elicit significant modulatory effects on CYP activities in rat and human liver. These developments indicate the importance of understanding the chem. mechanisms by which MDPs interact with CYPs. Thus, the presence of the MDP structure may undermine the potential clin. value of new drugs.
- 53Bardin, E.; Pastor, A.; Semeraro, M.; Golec, A.; Hayes, K.; Chevalier, B.; Berhal, F.; Prestat, G.; Hinzpeter, A.; Gravier-Pelletier, C.; Pranke, I.; Sermet-Gaudelus, I. Modulators of CFTR. Updates on clinical development and future directions. Eur. J. Med. Chem. 2021, 213, 113195, DOI: 10.1016/j.ejmech.2021.113195[Crossref], [PubMed], [CAS], Google Scholar53https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXjtVWisLs%253D&md5=347dc40d958b08ffae8e39271a78ca9cModulators of CFTR. Updates on clinical development and future directionsBardin, Emmanuelle; Pastor, Alexandra; Semeraro, Michaela; Golec, Anita; Hayes, Kate; Chevalier, Benoit; Berhal, Farouk; Prestat, Guillaume; Hinzpeter, Alexandre; Gravier-Pelletier, Christine; Pranke, Iwona; Sermet-Gaudelus, IsabelleEuropean Journal of Medicinal Chemistry (2021), 213 (), 113195CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)Cystic fibrosis (CF) is the most frequent life-limiting autosomal recessive disorder in the Caucasian population. It is due to mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Current symptomatic CF therapies, which treat the downstream consequences of CFTR mutations, have increased survival. Better knowledge of the CFTR protein has enabled pharmacol. therapy aiming to restore mutated CFTR expression and function. These CFTR "modulators" have revolutionised the CF therapeutic landscape, with the potential to transform prognosis for a considerable no. of patients. This review provides a brief summary of their mechanism of action and presents a thorough review of the results obtained from clin. trials of CFTR modulators.
- 54Keith, J. M.; Jones, W. M.; Tichenor, M.; Liu, J.; Seierstad, M.; Palmer, J. A.; Webb, M.; Karbarz, M.; Scott, B. P.; Wilson, S. J.; Luo, L.; Wennerholm, M. L.; Chang, L.; Rizzolio, M.; Rynberg, R.; Chaplan, S. R.; Breitenbucher, J. G. Preclinical characterization of the FAAH inhibitor JNJ-42165279. ACS Med. Chem. Lett. 2015, 6, 1204– 1208, DOI: 10.1021/acsmedchemlett.5b00353[ACS Full Text], [CAS], Google Scholar54https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhslGms73P&md5=fc681414ace29f39906fdd62c204114bPreclinical Characterization of the FAAH Inhibitor JNJ-42165279Keith, John M.; Jones, William M.; Tichenor, Mark; Liu, Jing; Seierstad, Mark; Palmer, James A.; Webb, Michael; Karbarz, Mark; Scott, Brian P.; Wilson, Sandy J.; Luo, Lin; Wennerholm, Michelle L.; Chang, Leon; Rizzolio, Michele; Rynberg, Raymond; Chaplan, Sandra R.; Breitenbucher, J. GuyACS Medicinal Chemistry Letters (2015), 6 (12), 1204-1208CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)The preclin. characterization of the aryl piperazinyl urea inhibitor of fatty acid amide hydrolase (FAAH) JNJ-42165279 I is described. JNJ-42165279 covalently inactivates the FAAH enzyme, but is highly selective with regard to other enzymes, ion channels, transporters, and receptors. JNJ-42165279 exhibited excellent ADME and pharmacodynamic properties as evidenced by its ability to block FAAH in the brain and periphery of rats and thereby cause an elevation of the concns. of anandamide (AEA), oleoyl ethanolamide (OEA), and palmitoyl ethanolamide (PEA). The compd. was also efficacious in the spinal nerve ligation (SNL) model of neuropathic pain. The combination of good phys., ADME, and PD properties of JNJ-42165279 supported it entering the clin. portfolio.
- 55Rose, W. C.; Marathe, P. H.; Jang, G. R.; Monticello, T. M.; Balasubramanian, B. N.; Long, B.; Fairchild, C. R.; Wall, M. E.; Wani, M. C. Novel fluoro-substituted camptothecins: in vivo antitumor activity, reduced gastrointestinal toxicity and pharmacokinetic characterization. Cancer Chemother. Pharmacol. 2006, 58, 73– 85, DOI: 10.1007/s00280-005-0128-y[Crossref], [PubMed], [CAS], Google Scholar55https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XjslGjsbg%253D&md5=97ecbd7d19b5e051255c5c0dc03b215aNovel fluoro-substituted camptothecins: in vivo antitumor activity, reduced gastrointestinal toxicity and pharmacokinetic characterizationRose, William C.; Marathe, Punit H.; Jang, Graham R.; Monticello, Thomas M.; Balasubramanian, Balu N.; Long, Byron; Fairchild, Craig R.; Wall, Monroe E.; Wani, Mansukh C.Cancer Chemotherapy and Pharmacology (2006), 58 (1), 73-85CODEN: CCPHDZ; ISSN:0344-5704. (Springer)Purpose: The novel fluoro-substituted camptothecin analog, BMS-286309, and its prodrug, BMS-422461, were evaluated for their pharmacol., toxicol., metabolic and pharmacokinetic developmental potential. Methods: In vitro and in vivo assays were used to assess the compds. for topoisomerase I activity, antitumor activity, gastrointestinal (GI) toxicity, and pharmacokinetic parameters. Results: BMS-286309-induced topoisomerase I-mediated DNA breaks in vitro and was similar in potency to camptothecin. Both BMS-286309 and -422461 were comparable to irinotecan regarding preclin. antitumor activity assessed in mice bearing distal site murine and human tumors. BMS-422461 was also found to be orally active. Both analogs were >100-fold more potent in vivo than irinotecan and both were superior to irinotecan with respect to toxicol. assessment of GI injury in mice. The generation of parent compd. from BMS-422461 was qual. similar in mouse, rat and human blood and liver S9 fractions. The percentage of BMS-286309 remaining as the active lactone form at equil. was comparable in mouse and human plasma. The pharmacokinetic profile in rat blood demonstrated that BMS-422461 was rapidly cleaved to BMS-286309. Conclusions: The favorable in vivo metabolic activation of BMS-422461, and the pharmacokinetic characteristics of BMS-286309, suggest that the good efficacy of BMS-422461 is derived from robust in vivo release of BMS-286309 in rodents and the likelihood that this biotransformation will be preserved in humans. The comparable antitumor activity of BMS-422461 to irinotecan, as well as reduced preclin. GI toxicity, make this novel camptothecin analog attractive for clin. development.
- 56Alig, L.; Alsenz, J.; Andjelkovic, M.; Bendels, S.; Bénardeau, A.; Bleicher, K.; Bourson, A.; David-Pierson, P.; Guba, W.; Hildbrand, S.; Kube, D.; Lübbers, T.; Mayweg, A. V.; Narquizian, R.; Neidhart, W.; Nettekoven, M.; Plancher, J.; Rocha, C.; Rogers-Evans, M.; Röver, S.; Schneider, G.; Taylor, S.; Waldmeier, P. Benzodioxoles: novel cannabinoid-1 receptor inverse agonists for the treatment of obesity. J. Med. Chem. 2008, 51, 2115– 2127, DOI: 10.1021/jm701487t[ACS Full Text], [CAS], Google Scholar56https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXjt1Wqsbg%253D&md5=ac2fb302fb7c3a7cf6c46994d87bd83aBenzodioxoles: Novel Cannabinoid-1 Receptor Inverse Agonists for the Treatment of ObesityAlig, Leo; Alsenz, Jochem; Andjelkovic, Mirjana; Bendels, Stefanie; Benardeau, Agnes; Bleicher, Konrad; Bourson, Anne; David-Pierson, Pascale; Guba, Wolfgang; Hildbrand, Stefan; Kube, Dagmar; Luebbers, Thomas; Mayweg, Alexander V.; Narquizian, Robert; Neidhart, Werner; Nettekoven, Matthias; Plancher, Jean-Marc; Rocha, Cynthia; Rogers-Evans, Mark; Roever, Stephan; Schneider, Gisbert; Taylor, Sven; Waldmeier, PiusJournal of Medicinal Chemistry (2008), 51 (7), 2115-2127CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The application of the evolutionary fragment-based de novo design tool TOPol. Assigning System (TOPAS), starting from a known CB1R (CB-1 receptor) ligand, followed by further refinement principles, including pharmacophore compliance, chem. tractability, and drug likeness, allowed the identification of benzodioxoles as a novel CB1R inverse agonist series. Extensive multidimensional optimization was rewarded by the identification of promising lead compds., showing in vivo activity. These compds. reversed the CP-55940-induced hypothermia in Naval Medical Research Institute (NMRI) mice and reduced body-wt. gain, as well as fat mass, in diet-induced obese Sprague-Dawley rats. Herein, we disclose the tools and strategies that were employed for rapid hit identification, synthesis and generation of structure-activity relationships, ultimately leading to the identification of (+)-[(R)-2-(2,4-dichloride-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone (I). Biochem., pharmacokinetic, and pharmacodynamic characteristics of I are discussed.
- 57(a) Boyle, C. D.; Chackalamannil, S.; Chen, L.; Dugar, S.; Pushpavanam, P.; Billard, W.; Binch, H.; Crosby, H.; Cohen-Williams, M.; Coffin, V. L.; Duffy, R. A.; Ruperto, V.; Lachowicz, J. E. Benzylidene ketal derivatives as M2 muscarinic receptor antagonists. Bioorg. Med. Chem. Lett. 2000, 10, 2727– 2730, DOI: 10.1016/S0960-894X(00)00553-9[Crossref], [PubMed], [CAS], Google Scholar.57ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXosFelsbk%253D&md5=c5a5fc7ae27902089c099213328b5e18Benzylidene ketal derivatives as M2 muscarinic receptor antagonistsBoyle, C. D.; Chackalamannil, S.; Chen, L.-Y.; Dugar, S.; Pushpavanam, P.; Billard, W.; Binch, H.; Crosby, G.; Cohen-Williams, M.; Coffin, V. L.; Duffy, R. A.; Ruperto, V.; Lachowicz, J. E.Bioorganic & Medicinal Chemistry Letters (2000), 10 (24), 2727-2730CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)Benzylidene ketal derivs. were investigated as selective M2 receptor antagonists for the treatment of Alzheimer's disease. Compd. I was discovered to have subnanomolar M2 receptor affinity and 100-fold selectivity against other muscarinic receptors. Also, I demonstrated in vivo efficacy in rodent models of muscarinic activity and cognition.(b) Boyle, C. D.; Chackalamannil, S.; Clader, J. W.; Greenlee, W. J.; Josien, H. B.; Kaminski, J. J.; Kozlowski, J. A.; McCombie, S. W.; Nazareno, D. V.; Tagat, J. R.; Wang, Y.; Zhou, G.; Billard, W.; Binch, H.; Crosby, G.; Cohen-Williams, M.; Coffin, V. L.; Cox, K. A.; Grotz, D. E.; Duffy, R. A.; Ruperto, V.; Lachowicz, J. E. Metabolic stabilization of benzylidene ketal M2 muscarinic receptor antagonists via halonaphthoic acid substitution. Bioorg. Med. Chem. Lett. 2001, 11, 2311– 2314, DOI: 10.1016/S0960-894X(01)00435-8[Crossref], [PubMed], [CAS], Google Scholar57bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXmt1yqu70%253D&md5=0232ced3ab4512f9be66a3b36a4adb8dMetabolic stabilization of benzylidene ketal M2 muscarinic receptor antagonists via halonaphthoic acid substitutionBoyle, C. D.; Chackalamannil, S.; Clader, J. W.; Greenlee, W. J.; Josien, H. B.; Kaminski, J. J.; Kozlowski, J. A.; McCombie, S. W.; Nazareno, D. V.; Tagat, J. R.; Wang, Y.; Zhou, G.; Billard, W.; Binch, H.; Crosby, G.; Cohen-Williams, M.; Coffin, V. L.; Cox, K. A.; Grotz, D. E.; Duffy, R. A.; Ruperto, V.; Lachowicz, J. E.Bioorganic & Medicinal Chemistry Letters (2001), 11 (17), 2311-2314CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)The potential toxicol. liabilities of a previously studied M2 muscarinic antagonist benzylidene ketal were addressed by replacing the methylenedioxyphenyl moiety with a p-methoxyphenyl group, resulting in M2 selective compds. such as (I). Several halogenated naphthamide derivs. of I were studied to improve the pharmacokinetic profile via blockage of oxidative metab. Compd. (II) demonstrated excellent M2 affinity and selectivity, human microsomal stability, and oral bioavailability in rodents and primates.
- 58(a) Franchini, S.; Sorbi, C.; Linciano, P.; Carnevale, G.; Tait, A.; Ronsisvalle, S.; Buccioni, M.; Del Bello, F.; Cilia, A.; Pirona, L.; Denora, N.; Iacobazzi, R. M.; Brasili, L. 1,3-Dioxane as a scaffold for potent and selective 5-HT1AR agonist with in-vivo anxiolytic, anti-depressant and anti-nociceptive activity. Eur. J. Med. Chem. 2019, 176, 310– 325, DOI: 10.1016/j.ejmech.2019.05.024[Crossref], [PubMed], [CAS], Google Scholar.58ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXpvFeis7o%253D&md5=c5601fb67fe50e79223f254f141097701,3-Dioxane as a scaffold for potent and selective 5-HT1AR agonist with in-vivo anxiolytic, anti-depressant and anti-nociceptive activityFranchini, Silvia; Sorbi, Claudia; Linciano, Pasquale; Carnevale, Gianluca; Tait, Annalisa; Ronsisvalle, Simone; Buccioni, Michela; Del Bello, Fabio; Cilia, Antonio; Pirona, Lorenza; Denora, Nunzio; Iacobazzi, Rosa Maria; Brasili, LivioEuropean Journal of Medicinal Chemistry (2019), 176 (), 310-325CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)A series of compds. generated by ring expansion/opening and mol. elongation/simplification of the 1,3-dioxolane scaffold were prepd. and tested for binding affinity at 5-HT1AR and α1 adrenoceptors. The compds. with greater affinity were selected for further functional studies. N-((2,2-diphenyl-1,3-dioxan-5-yl)methyl)-2-(2-methoxyphenoxy)ethan-1-ammonium hydrogen oxalate I emerged as highly potent full agonist at the 5-HT1AR (pKi 5-HT1A = 8.8; pD2 = 9.22, %Emax = 92). The pharmacokinetic data in rats showed that the orally administered I has a high biodistribution in the brain compartment. Thus, I was further investigated in-vivo, showing an anxiolytic and antidepressant effect. Moreover, in the formalin test, the above compd. was able to decrease the late response to the noxious stimulus, indicating a potential use in the treatment of chronic pain.(b) Linciano, P.; Sorbi, C.; Comitato, A.; Lesniak, A.; Bujalska-Zadrożny, M.; Pawłowska, A.; Bielenica, A.; Orzelska-Górka, J.; Kedzierska, E.; Biała, G.; Ronsisvalle, S.; Limoncella, S.; Casarini, L.; Cichero, E.; Fossa, P.; Satała, G.; Bojarski, A. J.; Brasili, L.; Bardoni, R.; Franchini, S. Identification of a potent and selective 5-HT1A receptor agonist with in vitro and in vivo antinociceptive activity. ACS Chem. Neurosci. 2020, 11, 4111– 4127, DOI: 10.1021/acschemneuro.0c00289[ACS Full Text], [CAS], Google Scholar58bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXisVCksb3O&md5=fa1038f2e60e9a0fe307c46316427a36Identification of a Potent and Selective 5-HT1A Receptor Agonist with In Vitro and In Vivo Antinociceptive ActivityLinciano, Pasquale; Sorbi, Claudia; Comitato, Antonella; Lesniak, Anna; Bujalska-Zadrozny, Magdalena; Pawlowska, Agata; Bielenica, Anna; Orzelska-Gorka, Jolanta; Kedzierska, Ewa; Biala, Grazyna; Ronsisvalle, Simone; Limoncella, Silvia; Casarini, Livio; Cichero, Elena; Fossa, Paola; Satala, Grzegorz; Bojarski, Andrzej J.; Brasili, Livio; Bardoni, Rita; Franchini, SilviaACS Chemical Neuroscience (2020), 11 (24), 4111-4127CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)Opioids are the gold std. drugs for the treatment of acute and chronic severe pain, although their serious side effects constitute a big limitation. In the search for new and safer drugs, 5-HT1AR agonists are emerging as potential candidates in pain relief therapy. In this work, we evaluated the affinity and activity of enantiomers of the two newly synthesized, potent 5-HT1AR agonists N-[(2,2-diphenyl-1,3-dioxolan-4-yl)methyl]-2-[2-(pyridin-4-yl)phenoxy]ethan-1-ammonium hydrogenoxalate (rac-1) and N-((2,2-diphenyl-1,3-dioxolan-4-yl)methyl)-2-(2-(1-methyl-1H-imidazol-5-yl)phenoxy)ethan-1-ammonium hydrogenoxalate (rac-2) in vitro and in vivo. The role of chirality in the interaction with 5-HT1AR was evaluated by mol. docking. The activity of the rac-1 was tested in mouse models of acute pain (hot plate) and severe tonic nociceptive stimulation (intraplantar formalin test). Rac-1 was active in the formalin test with a redn. in paw licking in both phases at 10 mg/kg, and its effect was abolished by the selective 5-HT1AR antagonist, WAY-100635. The eutomer (S)-1, but not the racemate, was active during the hot plate test at 10 and 20 mg/kg, and this effect was abolished by 30 min treatment with WAY-100635 at 30 min. Similarly to 8-OH-DPAT, (S)-1 evoked a slow outward current and depressed spontaneous glutamatergic transmission in superficial dorsal horn neurons, more effectively than rac-1. The eutomer (S)-1 showed promising developability properties, such as high selectivity over 5-HT subtypes, no interaction with the μ receptors, and low hepato- and cardiotoxicity. Therefore, (S)-1 may represent a potential candidate for the treatment of acute and chronic pain without having the adverse effects that are commonly assocd. with the classic opioid drugs.
- 59(a) Dunn, M. I. A new antihypertensive drug. JAMA, J. Am. Med. Assoc. 1981, 245, 1639– 1642, DOI: 10.1001/jama.245.16.1639[Crossref], [PubMed], [CAS], Google Scholar.59ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL3M7ksFKlsA%253D%253D&md5=afad866489d11a33f161808499465c14Guanadrel. A new antihypertensive drugDunn M I; Dunlap J LJAMA (1981), 245 (16), 1639-42 ISSN:0098-7484.Guanadrel sulfate, a new adrenergic neuron inhibitor similar to guanethidine sulfate, was tested on 199 outpatients by 11 investigators. The patients had mild, moderate, or severe hypertension as determined by diastolic blood pressures of 95 to 105, 106 to 114, and 115 to 120 mm Hg, respectively. Guanadrel was found to be an effective antihypertensive agent for all levels of hypertension. Since guanadrel has a short onset of action and a short offset of action, which prevents many of the side effects of guanathidine, the dosage could be adjusted rapidly and safely. At low doses side effects are infrequent. There was no organ toxicity and no CNS effect. Guanadrel should be an effective step II or step III drug for treatment of hypertension.(b) Hengstmann, J. H.; Falkner, F. C. Disposition of guanethidine during chronic oral therapy. Eur. J. Clin. Pharmacol. 1979, 15, 121– 125, DOI: 10.1007/BF00609875[Crossref], [PubMed], [CAS], Google Scholar.59bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaE1M7mvFCgsA%253D%253D&md5=fc3e3bd45a46c971db3ab8b704d3510eDisposition of guanethidine during chronic oral therapyHengstmann J H; Falkner F CEuropean journal of clinical pharmacology (1979), 15 (2), 121-5 ISSN:0031-6970.The plasma level and urinary excretion rate of guanethidine have been measured in 30 patients during oral maintenance therapy, and in 5 patients following discontinuous of therapy. A significant correlation was found between the daily average urinary excretion and the maintenance dose, although wide interindividual variation was noted among patients maintained on the same dose. A statistically significant correlation was also observed between the area under the plasma level curve during the dose interval and the oral maintenance dose. After discontinuation of chronic therapy, the half-life of 1.5 days of the initial phase of elimination was essentially in agreement with the half-life of almost 2 days determined in acute studies. In addition, a second phase of elimination with a half-life of 4 to 8 days was observed.(c) Finnerty, F. A., Jr.; Brogden, R. N. Guanadrel, A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in hypertension. Drugs 1985, 30, 22– 31, DOI: 10.2165/00003495-198530010-00003[Crossref], [PubMed], [CAS], Google Scholar59chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL2M3osVKntQ%253D%253D&md5=415c04855c3f572afdb3c4ed0292ee11Guanadrel. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in hypertensionFinnerty F A Jr; Brogden R NDrugs (1985), 30 (1), 22-31 ISSN:0012-6667.Guanadrel sulphate is an orally active peripheral sympathetic inhibitor (adrenergic neuron-blocking drug). In comparative studies, guanadrel was comparable in efficacy with guanethidine or methyldopa in mild to moderately severe hypertension, although generally it caused fewer central nervous system side effects than methyldopa and less orthostatic dizziness and diarrhoea than guanethidine. However, its efficacy in patients whose blood pressure remains inadequately controlled by other drugs (except diuretics alone) has yet to be adequately demonstrated. Guanadrel has a rapid onset of action and a half-life of about 10 hours, thus dose titration can be achieved more rapidly than with guanethidine, and twice daily administration is appropriate. Generally, guanadrel has been well tolerated, withdrawal of treatment due to adverse effects seldom being necessary. Thus, guanadrel appears to be a suitable alternative to methyldopa for the treatment of mild to moderately severe hypertension not controlled adequately by diuretics alone.
- 60(a) Satoh, E.; Kasahara, R.; Fukatsu, K.; Aoki, T.; Harayama, H.; Murata, T. Benzpyrimoxan: design, synthesis, and biological activity of a novel insecticide. J. Pestic. Sci. 2021, 46, 109– 114, DOI: 10.1584/jpestics.D20-069[Crossref], [PubMed], [CAS], Google Scholar.60ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhsVCjtLnE&md5=7ca20d0eefd2aa85f45963e2c1f55b06Benzpyrimoxan: design, synthesis, and biological activity of a novel insecticideSatoh, Eikoh; Kasahara, Ryota; Fukatsu, Kosuke; Aoki, Takao; Harayama, Hiroto; Murata, TetsuyaJournal of Pesticide Science (Tokyo, Japan) (2021), 46 (1), 109-114CODEN: JPSTCF; ISSN:1349-0923. (Pesticide Science Society of Japan)Benzpyrimoxan (5-(1,3-dioxan-2-yl)-4-{[4-(trifluoromethyl)phenyl]methoxy}pyrimidine, NNI-1501) was discovered as a novel insecticide structurally characterized by a pyrimidine deriv. substituted with 1,3-dioxanyl and 4-trifluoromethylbenzyloxy groups. The compd. showed remarkable activity against nymphs of rice planthoppers, including strains resistant to existing insecticides. Furthermore, benzpyrimoxan had low adverse effects on pollinators and beneficial arthropods. Because of these features, benzpyrimoxan is expected to be a suitable part of an integrated pest management strategy. In this report, the history of the discovery to reach benzpyrimoxan and details of the structure-activity relationships are described.(b) Umetsu, N.; Shirai, Y. Development of novel pesticides in the 21st century. J. Pestic. Sci. 2020, 45, 54– 74, DOI: 10.1584/jpestics.D20-201[Crossref], [PubMed], [CAS], Google Scholar60bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXit1Knu7vE&md5=fb35005da013ff4d48214812839f4752Development of novel pesticides in the 21st centuryUmetsu, Noriharu; Shirai, YuichiJournal of Pesticide Science (Tokyo, Japan) (2020), 45 (2), 54-74CODEN: JPSTCF; ISSN:1349-0923. (Pesticide Science Society of Japan)A review. General trends and strategies for novel pesticides are summarized. Global pesticide sales and pesticide discovery research are also briefly ed. At least 105 chem. pesticides have been launched during the past decade or are under development: 43 fungicides, 34 insecticides/acaricides, 6 nematicides, 21 herbicides, and 1 herbicide safener. Most of them are safe to humans and environmentally friendly. The most developed fungicides are SDHI (succinate dehydrogenase inhibitors), DMI (demethylation inhibitors), QoI (quinone outside inhibitors), and QiI (quinone inside inhibitors). Due to the development of resistance to fungicides with existing modes of action, many fungicides possessing various novel modes of action have been launched or are under development. The trend of insecticide development is changing from organophosphorus, carbamate, and synthetic pyrethroids to nicotinic and diamide insecticides. During the past decade, compds. possessing a variety of novel modes of action have also been launched or are under development. Flupyradifurone and flupyrimin, exhibiting extremely low honeybee toxicity, have been developed and subjected to practical use. Herbicides possessing varied modes of action, such as acetolactate synthase, p-hydroxyphenylpyruvate dioxygenase, protoporphyrinogen oxidase, and very-long-chain fatty acid elongase.
- 61(a) McAtee, L. C.; Sutton, S. W.; Rudolph, D. A.; Li, X.; Aluisio, L. E.; Phuong, V. K.; Dvorak, C. A.; Lovenberg, T. W.; Carruthers, N. I.; Jones, T. K. Novel substituted 4-phenyl-[1,3]dioxanes: potent and selective orexin receptor 2 (OX2R) antagonists. Bioorg. Med. Chem. Lett. 2004, 14, 4225– 4229, DOI: 10.1016/j.bmcl.2004.06.032[Crossref], [PubMed], [CAS], Google Scholar.61ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXlvVWjsbg%253D&md5=fe754c8f27a856d307d1e27caf3f6806Novel substituted 4-phenyl-[1,3]dioxanes: potent and selective orexin receptor 2 (OX2R) antagonistsMcAtee, Laura C.; Sutton, Steven W.; Rudolph, Dale A.; Li, Xiaobing; Aluisio, Leah E.; Phuong, Victor K.; Dvorak, Curt A.; Lovenberg, Timothy W.; Carruthers, Nicholas I.; Jones, Todd K.Bioorganic & Medicinal Chemistry Letters (2004), 14 (16), 4225-4229CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science B.V.)Orexins, also termed hypocretins, consist of two neuropeptide agonists (orexin A and B) interacting with two known G-protein coupled receptors (OX1R and OX2R). In addn. to other biol. functions, the orexin-2 receptor is thought to be an important modulator of sleep and wakefulness. Herein we describe a series of novel, selective OX2R antagonists consisting of substituted 4-phenyl-[1,3]dioxanes. One such antagonist is 1-(2,4-dibromo-phenyl)-3-((4S,5S)-2,2-dimethyl-4-phenyl-[1,3]dioxan-5-yl)-urea (I), which is bound by the OX2R with a pKi of 8.3, has a pKb of 7.9, and is 600-fold selective for the OX2R over the OX1R.(b) Letavic, M. A.; Bonaventure, P.; Carruthers, N. I.; Dugovic, C.; Koudriakova, T.; Lord, B.; Lovenberg, T. W.; Ly, K. S.; Mani, N. S.; Nepomuceno, D.; Pippel, D. J.; Rizzolio, M.; Shelton, J. E.; Shah, C. R.; Shireman, B. T.; Young, L. K.; Yun, S. Novel octahydropyrrolo[3,4-c]pyrroles are selective orexin-2 antagonists: SAR leading to a clinical candidate. J. Med. Chem. 2015, 58, 5620– 5636, DOI: 10.1021/acs.jmedchem.5b00742[ACS Full Text], [CAS], Google Scholar61bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVansL%252FP&md5=6d8785a362aab57c84f6a6db0775d84eNovel Octahydropyrrolo[3,4-c]pyrroles Are Selective Orexin-2 Antagonists: SAR Leading to a Clinical CandidateLetavic, Michael A.; Bonaventure, Pascal; Carruthers, Nicholas I.; Dugovic, Christine; Koudriakova, Tatiana; Lord, Brian; Lovenberg, Timothy W.; Ly, Kiev S.; Mani, Neelakandha S.; Nepomuceno, Diane; Pippel, Daniel J.; Rizzolio, Michele; Shelton, Jonathan E.; Shah, Chandra R.; Shireman, Brock T.; Young, Lana K.; Yun, SujinJournal of Medicinal Chemistry (2015), 58 (14), 5620-5636CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The preclin. characterization of novel octahydropyrrolo[3,4-c]pyrroles that are potent and selective orexin-2 antagonists is described. Optimization of physicochem. and DMPK properties led to the discovery of compds. with tissue distribution and duration of action suitable for evaluation in the treatment of primary insomnia. These selective orexin-2 antagonists are proven to promote sleep in rats, and this work ultimately led to the identification of a compd. that progressed into human clin. trials for the treatment of primary insomnia. The synthesis, SAR, and optimization of the pharmacokinetic properties of this series of compds. as well as the identification of the clin. candidate I are described herein.
- 62(a) Trabocchi, A.; Menchi, G.; Guarna, F.; Machetti, F.; Scarpi, D.; Guarna, A. Design, synthesis, and applications of 3-aza-6,8-dioxabicyclo[3.2.1]octane-based scaffolds for peptidomimetic chemistry. Synlett 2006, 2006, 0331– 0353, DOI: 10.1055/s-2006-926249 .(b) Trabocchi, A.; Cini, N.; Menchi, G.; Guarna, A. A new bicyclic proline-mimetic amino acid. Tetrahedron Lett. 2003, 44, 3489– 3492, DOI: 10.1016/S0040-4039(03)00663-4[Crossref], [CAS], Google Scholar.62bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXislejurc%253D&md5=384064db208f320f0afa5df534e84949A new bicyclic proline-mimetic amino acidTrabocchi, Andrea; Cini, Nicoletta; Menchi, Gloria; Guarna, AntonioTetrahedron Letters (2003), 44 (17), 3489-3492CODEN: TELEAY; ISSN:0040-4039. (Elsevier Science Ltd.)Constrained bicyclic α-amino acids I-IV as proline-mimetics were synthesized. For example, I and II were synthesized in several steps from D-α,β-isopropylidene-glycerol triflate and O-protected L- or D-serinol derivs. H2NCH(CH2OR)CH2OH (R = SiMe2Bu-t, CH2Ph), thus allowing the prepn. of either D- or L-proline mimetics. Similarly, III and IV were prepd. from L-α,β-isopropylidene-glycerol triflate. I-IV were prepd. as N-Fmoc-amino acid suitable for solid-phase peptide synthesis.(c) Trabocchi, A.; Menchi, G.; Danieli, E.; Guarna, A. Synthesis of a bicyclic δ-amino acid as a constrained Gly-Asn dipeptide isostere. Amino Acids 2008, 35, 37– 44, DOI: 10.1007/s00726-007-0636-7[Crossref], [PubMed], [CAS], Google Scholar.62chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXmslWjt7w%253D&md5=b60bf533ab4a13275eefd2ce9f34e0ccSynthesis of a bicyclic δ-amino acid as a constrained Gly-Asn dipeptide isostereTrabocchi, A.; Menchi, G.; Danieli, E.; Guarna, A.Amino Acids (2008), 35 (1), 37-44CODEN: AACIE6; ISSN:0939-4451. (Springer Wien)δ-Amino acids are very attractive in drug discovery, esp. in the peptidomimetic area, because of their capability to act as dipeptide isosteres and reverse turn mimetics. Herein, the authors report the synthesis of a rigid δ-amino acid constrained by a 3-aza-6,8-dioxabicyclo[3.2.1]octane-based scaffold, which can be considered as a Gly-Asn dipeptide mimetic. Key steps are the condensation of glycidol and tartaric acid derivs., and the intramol. trans-acetalization of the oxidized adduct to give the bicyclic δ-amino acid. For example, L-tartaric acid deriv. as a starting material afforded the Gly-D-Asn isostere, and similarly, the enantiomeric D-tartaric acid deriv. provided the corresponding Gly-D-Asn isostere.(d) Machetti, F.; Bucelli, I.; Indiani, G.; Guarna, A. Neat reaction of carboxylic acid methyl esters and amines for efficient parallel synthesis of scaffold amide libraries. C. R. Chim. 2003, 6, 631– 633, DOI: 10.1016/S1631-0748(03)00097-3[Crossref], [CAS], Google Scholar.62dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXmvV2lu7g%253D&md5=62eab404e0791d43468f2844c1873690Neat reaction of carboxylic acid methyl esters and amines for efficient parallel synthesis of scaffold amide librariesMachetti, Fabrizio; Bucelli, Ilaria; Indiani, Giovanni; Guarna, AntonioComptes Rendus Chimie (2003), 6 (5-6), 631-633CODEN: CRCOCR; ISSN:1631-0748. (Editions Scientifiques et Medicales Elsevier)Efficient synthesis of unsubstituted and substituted amides is described. The reaction is characterized by its mildness and ease of work-up. A library of amides, was prepd. by heating esters I [X = O, S] with various amines.(e) Cini, N.; Danieli, E.; Menchi, G.; Trabocchi, A.; Bottoncetti, A.; Raspanti, S.; Pupi, A.; Guarna, A. 3-Aza-6,8-dioxabicyclo[3.2.1]octanes as new enantiopure heteroatom-rich tropane-like ligands of human dopamine transporter. Bioorg. Med. Chem. 2006, 14, 5110– 5120, DOI: 10.1016/j.bmc.2006.04.019[Crossref], [PubMed], [CAS], Google Scholar62ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XlvFyrt7o%253D&md5=a385832e3ddf35b45d74f02cde14ff303-Aza-6,8-dioxabicyclo[3.2.1]octanes as new enantiopure heteroatom-rich tropane-like ligands of human dopamine transporterCini, Nicoletta; Danieli, Elisa; Menchi, Gloria; Trabocchi, Andrea; Bottoncetti, Anna; Raspanti, Silvia; Pupi, Alberto; Guarna, AntonioBioorganic & Medicinal Chemistry (2006), 14 (15), 5110-5120CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)CNS diseases such as Parkinson, schizophrenia, and attention deficit hyperactivity disorder (ADHD) are characterized by a significant alteration of dopamine transporter (DAT) d. Thus, the development of compds. that are able to selectively interact with DAT is of great interest. Herein we describe the design and synthesis of a new set of 3-aza-6,8-dioxabicyclo[3.2.1]octanes having a tropane-like structure with addnl. heteroatoms at positions 3 and 6. The compds. were evaluated for their in vitro receptor binding properties toward human dopamine (hDAT) and serotonin (hSERT) transporters using [3H]WIN35,428 and [3H]citalopram as specific radioligands, resp. Biol. assays revealed that some compds. having the N-3 atom substituted with aryl groups possess significant affinity and selectivity for monoamine transporters, and in particular, compd. 5d displayed an IC50 of 21 nM toward DAT, and a good selectivity toward SERT (IC50 = 1042 nM). These results suggest that 3-aryl-3-aza-6,8-dioxabicyclo[3.2.1]octanes may represent a new class of DAT ligands.
- 63(a) Sherwood, J.; De bruyn, M.; Constantinou, A.; Moity, L.; McElroy, C. R.; Farmer, T. J.; Duncan, T.; Raverty, W.; Hunt, A. J.; Clark, J. H. Dihydrolevoglucosenone (Cyrene) as a bio-based alternative for dipolar aprotic solvents. Chem. Commun. 2014, 50, 9650– 9652, DOI: 10.1039/C4CC04133J[Crossref], [PubMed], [CAS], Google Scholar.63ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtVOnurnO&md5=4159e1a7d7eab47f2d05e686358dbe62Dihydrolevoglucosenone (Cyrene) as a bio-based alternative for dipolar aprotic solventsSherwood, James; De Bruyn, Mario; Constantinou, Andri; Moity, Laurianne; McElroy, C. Rob; Farmer, Thomas J.; Duncan, Tony; Raverty, Warwick; Hunt, Andrew J.; Clark, James H.Chemical Communications (Cambridge, United Kingdom) (2014), 50 (68), 9650-9652CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)Dihydrolevoglucosenone (Cyrene) is a bio-based mol., derived in two simple steps from cellulose, which demonstrates significant promise as a dipolar aprotic solvent. The dipolarity of dihydrolevoglucosenone is similar to NMP, DMF and sulfolane. Dihydrolevoglucosenone demonstrates similar performance to NMP in a fluorination reaction and the Menschutkin reaction.(b) Hughes, L.; McElroy, C. R.; Whitwood, A. C.; Hunt, A. J. Development of pharmaceutically relevant biobased intermediates though aldol condensation and Claisen-Schmidt reactions of dihydrolevoglucosenone (Cyrene®). Green Chem. 2018, 20, 4423– 4427, DOI: 10.1039/C8GC01227J[Crossref], [CAS], Google Scholar.63bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtVeisbjL&md5=e703ec22ec55663a5e18b062d7d81aecDevelopment of pharmaceutically relevant bio-based intermediates though aldol condensation and Claisen-Schmidt reactions of dihydrolevoglucosenone (Cyrene)Hughes, Liam; McElroy, Con R.; Whitwood, Adrian C.; Hunt, Andrew J.Green Chemistry (2018), 20 (19), 4423-4427CODEN: GRCHFJ; ISSN:1463-9262. (Royal Society of Chemistry)Dihydrolevoglucosenone (Cyrene) has been successfully utilized as a bio-based platform mol. for the synthesis of pharmaceutically relevant intermediates through aldol condensation reactions. Utilizing sustainable synthetic methodologies, the self-aldol condensation reaction of Cyrene was achieved in high purity, with isolated yields of 81.3%. Claisen-Schmidt reactions with a range of arom. and heteroarom. aldehydes yielded several previously unreported Cyrene-based compds., characterized by single-crystal X-ray diffraction, FT-IR, NMR and MS.(c) Liu, X.; Carr, P.; Gardiner, M. G.; Banwell, M. G.; Elbanna, A. H.; Khalil, Z. G.; Capon, R. J. Levoglucosenone and its pseudoenantiomer iso-levoglucosenone as scaffolds for drug discovery and development. ACS Omega 2020, 5, 13926– 13939, DOI: 10.1021/acsomega.0c01331[ACS Full Text], [CAS], Google Scholar63chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtVyrt7nM&md5=146e93da113016acdb9ce2d6966d6bb2Levoglucosenone and Its Pseudo-enantiomer iso-Levoglucosenone as Scaffolds for Drug Discovery and DevelopmentLiu, Xin; Carr, Paul; Gardiner, Michael G.; Banwell, Martin G.; Elbanna, Ahmed H.; Khalil, Zeinab G.; Capon, Robert J.ACS Omega (2020), 5 (23), 13926-13939CODEN: ACSODF; ISSN:2470-1343. (American Chemical Society)The bio-derived platform mol. levoglucosenone (LGO) and its readily prepd. pseudo-enantiomer (iso-LGO) have each been subjected to α-iodination reactions with the product halides then being engaged in palladium-catalyzed Ullmann cross-coupling reactions with various bromonitropyridines. The corresponding α-pyridinylated derivs., e.g. I, are produced as a result. Biol. screening of such products reveals that certain of them display potent and selective antimicrobial and/or cytotoxic properties. In contrast, the aza-indoles obtained by reductive cyclization of compds. such as 11 and 12 are essentially inactive in these respects. Preliminary mode-of-action studies are reported.
- 64(a) Sensi, P. History of the development of rifampin. Clin. Infect. Dis. 1983, 5, S402– S406, DOI: 10.1093/clinids/5.Supplement_3.S402 .(b) Wehrli, W.; Staehelin, M. Rifamycins and other ansamycins. Mechanism of Action of Antimicrobial and Antitumor Agents. Antibiotics. 1975, 3, 252– 268, DOI: 10.1007/978-3-642-46304-4_16
- 65(a) Oppolzer, W.; Prelog, V.; Sensi, P. The composition of rifamycin B and related rifamycins. Experientia 1964, 20, 336– 339, DOI: 10.1007/BF02171084[Crossref], [PubMed], [CAS], Google Scholar.65ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF2cXkvVCitbY%253D&md5=713bd4fd9add1713aad3c73a9aecc4a3Structure of rifomycin B and related rifomycinsOppolzer, W.; Prelog, V.; Sensi, P.Experientia (1964), 20 (6), 336-9CODEN: EXPEAM; ISSN:0014-4754.Structure I is proposed for rifomycin B, based on nuclear magnetic resonance, infrared, ultraviolet spectra, and chem. data for I and derived compds.(b) Leitich, J.; Oppolzer, W.; Prelog, V. On the configuration of rifamycin B and related rifamycins. Experientia 1964, 20, 343– 344, DOI: 10.1007/BF02171086[Crossref], [PubMed], [CAS], Google Scholar65bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF2cXkvFWqsLY%253D&md5=2d134d53f92202a2244923820c3d4150Configuration of rifamycin B and related rifamycinsLeitich, J.; Oppolzer, W.; Prelog, V.Experientia (1964), 20 (6), 343-4CODEN: EXPEAM; ISSN:0014-4754.The relative configurations of rifamycin B (I) and related rifamycins have been detd. by x-ray analysis, which gives information also about the relative configuration of the 9 asym. C-atoms (C12 and C20 to C27) and in part by nuclear magnetic resonance spectroscopy. The abs. configuration has been derived from the configuration of a degradation product, the dextrorotatory α,α'-dimethyl-pimelic acid, and was recognized as S-configuration.
- 66Bacchi, A.; Pelizzi, G.; Nebuloni, M.; Ferrari, P. Comprehensive study on structure-activity relationships of rifamycins: discussion of molecular and crystal structure and spectroscopic and thermochemical properties of rifamycin O. J. Med. Chem. 1998, 41, 2319– 2332, DOI: 10.1021/jm970791o[ACS Full Text], [CAS], Google Scholar66https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXjtlygtrk%253D&md5=a00455a0e5b2806d198df44f66f28761Comprehensive study on structure-activity relationship of rifamycins: discussion of molecular and crystal structure and spectroscopic and thermochemical properties of rifamycin OBacchi, Alessia; Pelizzi, Giancarlo; Nebuloni, Marino; Ferrari, PietroJournal of Medicinal Chemistry (1998), 41 (13), 2319-2332CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The mechanism of action of rifamycins against bacterial DNA-dependent RNA polymerase has been explained on the basis of the spatial arrangement of four oxygens which can form hydrogen bonds with the enzyme. Structural descriptors are derived from X-ray diffraction crystal structures of 25 active and nonactive rifamycins. Principal component anal. is used to find the combination of structural parameters which better discriminate between active and nonactive rifamycins. Two possible mechanisms of mol. rearrangement are described which can convert nonactive into active conformations. The energy involved for conformational rearrangements is studied by mol. modeling techniques. Me C34 is found to play a key role for detg. the geometry of the pharmacophore. Rifamycin O, reported to be active, is obtained by oxidn. of rifamycin B and is studied by X-ray single-crystal diffractometry, by soln. IR and NMR spectroscopy, and by thermal anal. Surprisingly the oxidn. process results are totally stereospecific, and an explanation is given based on soln. spectroscopic evidence. The conformation found in the solid state is typical of nonactive compds., and mol. mechanics calcns. show that a mol. rearrangement to the active conformation would require about 15 kcal/mol. Thermal anal. confirms that rifamycin O has a sterically constrained conformation. Therefore, it is likely that the antibiotic activity of rifamycin O is due either to chem. modification prior to reaching the enzyme or to conformational activation.
- 67Bergamini, N.; Fowst, G. Rifamycin SV. A review. Arzneim.-Forsch. 1965, 15 (Suppl), 951– 1002[CAS], Google Scholar67https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF2MXksl2rsb4%253D&md5=3d10d69f2e61468abed76d9383049f90Rifamycin SVBergamini, N.; Fowst, G.Arzneimittel-Forschung (1965), 15 (8a), 951-1002CODEN: ARZNAD; ISSN:0004-4172.400 refs.
- 68Rode, H. B.; Lade, D. M.; Grée, R.; Mainkar, P. S.; Chandrasekhar, S. Strategies towards the synthesis of anti-tuberculosis drugs. Org. Biomol. Chem. 2019, 17, 5428– 5459, DOI: 10.1039/C9OB00817A[Crossref], [PubMed], [CAS], Google Scholar68https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXoslKqs7s%253D&md5=8d8e84286dae61acd4adfe38142cf45fStrategies towards the synthesis of anti-tuberculosis drugsRode, Haridas B.; Lade, Dhanaji M.; Gree, Rene; Mainkar, Prathama S.; Chandrasekhar, SrivariOrganic & Biomolecular Chemistry (2019), 17 (22), 5428-5459CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)A review. Antituberculosis drugs have captured the attention of the scientific community due to the emergence of drug resistance. Hence, the development of new analogs and new drugs which can treat drug-resistant tuberculosis is required. In this report, we reviewed the strategies towards the synthesis of antituberculosis drugs. These strategies include semisynthetic approaches, resoln. based strategies, microbial transformations, solid phase synthesis, and asym. synthesis. As stereochem. is an important hallmark of many drugs, the strategies based on asym. synthesis are described in detail. The emphasis on semisynthetic approaches is given for aminoglycoside antibiotics.
- 69(a) Loos, U.; Musch, E.; Jensen, J. C.; Mikus, G.; Schwabe, H. K.; Eichelbaum, M. Pharmacokinetics of oral and intravenous rifampicin during chronic administration. Klin. Wochenschr. 1985, 63, 1205– 1211, DOI: 10.1007/BF01733779[Crossref], [PubMed], [CAS], Google Scholar.69ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL287hs1GltA%253D%253D&md5=0337fe0975b63bd2bd6ff69435d9e02ePharmacokinetics of oral and intravenous rifampicin during chronic administrationLoos U; Musch E; Jensen J C; Mikus G; Schwabe H K; Eichelbaum MKlinische Wochenschrift (1985), 63 (23), 1205-11 ISSN:0023-2173.We investigated the pharmacokinetics of rifampicin and its major metabolites, 25-desacetylrifampicin and 3-formylrifampicin, in two groups of six patients with active pulmonary tuberculosis, who received either multiple oral or intravenous rifampicin therapy in combination with intravenous isoniazid and ethambutol. Serum concentrations of rifampicin were each determined after a single oral and intravenous test dose of 600 mg rifampicin at the beginning and after 1 and 3 weeks of tuberculostatic treatment. Analysis of rifampicin and its metabolites was performed by high-pressure liquid chromatography. It was found that, due to autoinduction of its metabolizing hepatic enzymes, the systemic clearance of rifampicin increased from 5.69 to 9.03 l/h after 3 weeks of multiple dosing. The volume of distribution of the drug was constant over the period of this study. The bioavailability of the active, orally administered rifampicin decreased from 93% after the first single oral dose to 68% after 3 weeks of oral and intravenous rifampicin therapy. Relating to the increase in systemic (hepatic) clearance, a bioavailability no lower than 90% can be predicted. The reduction to 68% indicates that, in addition to an increase of hepatic metabolism, an induction of a prehepatic "first-pass" effect resulted from multiple rifampicin doses. Our study of rifampicin metabolites confirm that prehepatic metabolism was induced, since a higher metabolic ratio resulted after the oral doses than after the intravenous rifampicin test doses. A preabsorptive process can therefore be excluded as a cause of reduced bioavailability.(b) Acocella, G. Clinical pharmacokinetics of rifampicin. Clin. Pharmacokinet. 1978, 3, 108– 127, DOI: 10.2165/00003088-197803020-00002[Crossref], [PubMed], [CAS], Google Scholar69bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE1cXktFKms74%253D&md5=b7a697fe3dda6d470e0cb55306013207Clinical pharmacokinetics of rifampicinAcocella, G.Clinical Pharmacokinetics (1978), 3 (2), 108-27CODEN: CPKNDH; ISSN:0312-5963.A review with many refs. of rifampicin (I) [13292-46-1] clin. pharmacokinetics.
- 70Campbell, E. A.; Korzheva, N.; Mustaev, A.; Murakami, K.; Nair, S.; Goldfarb, A.; Darst, S. A. Structural mechanism for rifampicin inhibition of bacterial RNA polymerase. Cell 2001, 104, 901– 912, DOI: 10.1016/S0092-8674(01)00286-0[Crossref], [PubMed], [CAS], Google Scholar70https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXisVyis7s%253D&md5=e64b9de4f4f6f832d481608b1324b48fStructural mechanism for rifampicin inhibition of bacterial RNA polymeraseCampbell, Elizabeth A.; Korzheva, Nataliya; Mustaev, Arkady; Murakami, Katsuhiko; Nair, Satish; Goldfarb, Alex; Darst, Seth A.Cell (Cambridge, MA, United States) (2001), 104 (6), 901-912CODEN: CELLB5; ISSN:0092-8674. (Cell Press)Rifampicin (Rif) is one of the most potent and broad spectrum antibiotics against bacterial pathogens and is a key component of anti-tuberculosis therapy, stemming from its inhibition of the bacterial RNA polymerase (RNAP). We detd. the crystal structure of Thermus aquaticus core RNAP complexed with Rif. The inhibitor binds in a pocket of the RNAP β subunit deep within the DNA/RNA channel, but more than 12 Å away from the active site. The structure, combined with biochem. results, explains the effects of Rif on RNAP function and indicates that the inhibitor acts by directly blocking the path of the elongating RNA when the transcript becomes 2 to 3 nt in length.
- 71Brogden, R. N.; Fitton, A. Rifabutin. Drugs 1994, 47, 983– 1009, DOI: 10.2165/00003495-199447060-00008[Crossref], [PubMed], [CAS], Google Scholar71https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXls12ntbY%253D&md5=a8648ab5e2878b0ca2c47b13420d7725Rifabutin: a review of its antimicrobial activity, pharmacokinetic properties and therapeutic efficacyBrogden, Rex N.; Fitton, AndrewDrugs (1994), 47 (6), 983-1009CODEN: DRUGAY; ISSN:0012-6667.A review, with approx. 150 refs. Rifabutin is a deriv. of rifamycin S with activity against mycobacteria including atypical organisms such as Mycobacterium avium and M. intracellulare, also referred to as Mycobacterium avium-intracellulare complex (MAC). To date, rifabutin is the only drug to have been studied in large prospective placebo-controlled trials that has been shown to significantly reduce the incidence of disseminated MAC infection when administered prophylactically as a single agent to patients with acquired immune deficiency syndrome (AIDS). Initial studies also indicate that rifabutin may be a useful component of multiple drug regimens for the treatment of MAC infection, although further studies combining rifabutin with other recently available antimycobacterial drugs are required to det. the most effective regimens. When rifabutin is combined with at least two other antimycobacterial drugs, the combination appears to be of similar efficacy to rifampicin (rifampin)-contg. regimens in patients with newly diagnosed pulmonary tuberculosis. Since available therapy for MAC infection in patients with AIDS is still suboptimal, rifabutin, at present the only first-line agent for prophylaxis against disseminated MAC infection in patients with advanced human immunodeficiency virus (HIV) infection, has the potential to make a valuable contribution to the continuing attempts to preserve the quality of life of patients with AIDS.
- 72(a) Skinner, M. H.; Blaschke, T. F. Clinical pharmacokinetics of rifabutin. Clin. Pharmacokinet. 1995, 28, 115– 125, DOI: 10.2165/00003088-199528020-00003[Crossref], [PubMed], [CAS], Google Scholar.72ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2M3lsVOltQ%253D%253D&md5=f84f607d888d36c507d0983f02f88ce1Clinical pharmacokinetics of rifabutinSkinner M H; Blaschke T FClinical pharmacokinetics (1995), 28 (2), 115-25 ISSN:0312-5963.The clinical effectiveness of rifabutin for prophylaxis of disseminated Mycobacterium avium complex infection has recently been demonstrated in HIV-positive patients with low CD4 counts. Rifabutin is a newly marketed, semisynthetic antimycobacterial agent similar to rifampicin (rifampin) in structure and activity. However, rifabutin has important pharmacokinetic differences compared with rifampicin. Rifabutin has relatively low oral bioavailability; about 20% after single dose administration. With long term administration rifabutin induces its own metabolism and the metabolism of some other drugs. The elimination half-life of rifabutin is long (45 hours) but, as a result of a very large volume of distribution (> 9 L/kg), average plasma concentrations remain relatively low after repeated administration of standard doses. In vitro rifabutin is more active against M. avium-intracellulare complex and at least as active against M. tuberculosis as rifampicin. In vivo the advantage of rifabutin is less apparent due to its lower plasma concentrations at equivalent doses. Adverse effects are unusual at the recommended oral dosage of 300 mg/day, but become common as the total daily dose approaches 1 g. Dose-limiting toxicity consists of a polyarthralgia/arthritis syndrome, possibly complicated by uveitis. More clinical studies are needed to establish the role of rifabutin in combination therapy for M. avium-intracellulare complex and other mycobacterial infections.(b) Blaschke, T. F.; Skinner, M. H. The clinical pharmacokinetics of rifabutin. Clin. Infect. Dis. 1996, 22, S15– S22, DOI: 10.1093/clinids/22.Supplement_1.S15[Crossref], [PubMed], [CAS], Google Scholar72bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XisVGgur0%253D&md5=43441f1ef61aa1f820fe3b85022c8ef2The clinical pharmacokinetics of rifabutinBlaschke, Terrence F.; Skinner, Michael H.Clinical Infectious Diseases (1996), 22 (Suppl. 1), S15-S22CODEN: CIDIEL; ISSN:1058-4838. (University of Chicago Press)A review with 28 refs. Rifabutin is structurally similar to rifampin, but there are important pharmacokinetic differences between the 2 drugs. Rifabutin is more lipid sol. than is rifampin, resulting in more-extensive tissue uptake, a larger vol. of distribution, lower max. plasma concns., lower trough concns., a longer terminal half-life, and higher tissue-to-plasma drug concn. ratios. The oral bioavailability of rifabutin is low. Like rifampin, rifabutin induces its own metab. during multiple dosing. Rifabutin is extensively metabolized. The 2 major metabolites of rifabutin contribute to its antimicrobial activity.
- 73Stahelin, H. F.; von Wartburg, A. The chemical and biological route from podophyllotoxin glucoside to etoposide: ninth Cain Memorial Award Lecture. Cancer Res. 1991, 51, 5– 15[PubMed], [CAS], Google Scholar73https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK3M7gsFKktQ%253D%253D&md5=3a2d99d15f60c943d3c6cf31ec8f15e2The chemical and biological route from podophyllotoxin glucoside to etoposide: ninth Cain memorial Award lectureStahelin H F; von Wartburg ACancer research (1991), 51 (1), 5-15 ISSN:0008-5472.There is no expanded citation for this reference.
- 74(a) Joel, S. P.; Clark, P. I.; Heap, L.; Webster, L.; Robbins, S.; Craft, H.; Slevin, M. L. Pharmacological attempts to improve the bioavailability of oral etoposide. Cancer Chemother. Pharmacol. 1995, 37, 125– 133, DOI: 10.1007/BF00685639[Crossref], [PubMed], [CAS], Google Scholar.74ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XlvFyksQ%253D%253D&md5=d2bc8bca898d0a301999a8c1a234149ePharmacological attempts to improve the bioavailability of oral etoposideJoel, Simon P.; Clark, Peter I.; Heap, Laura; Webster, Lynn; Robbins, Sallie; Craft, Helen; Slevin, Maurice L.Cancer Chemotherapy and Pharmacology (1995), 37 (1/2), 125-33CODEN: CCPHDZ; ISSN:0344-5704. (Springer)Etoposide demonstrates incompletes and variable bioavailability after oral dosing, which may be due to its concn. and pH-dependent stability in artificial gastric and intestinal fluids. The use of agents that may influence etoposide stability and, thereby, bioavailability, was investigated in a no. of clin. studies. Drugs that influence the rate of gastric emptying, while modulating the time of drug absorption, did not significantly alter the etoposide area under the concn.-time curve (AUC) or bioavailability. Specifically, metoclopramide had little effect on the etoposide absorption profile and did not significantly alter the AUC (AUC with etoposide alone, 68.4 vs. 74.3 μg mL-1 h with metoclopramide), suggesting that in most patients the drug is already emptied rapidly from the stomach. In contrast, propantheline produced a dramatic effect on etoposide absorption, delaying the time of maximal concn. tmax from 1.1 to 3.5 h , but again without a significant improvement in drug AUC or bioavailability across the 24 h study period (AUC with etoposide alone 78.3, vs. 88.1 μg mL-1 h with propantheline). The effect of these drugs on the absorption of oral paracetamol, a drug included in the study as a marker of gastric emptying, was exactly the same as that found for etoposide, with no change in AUC being obsd. after metoclopramide or propantheline administration but a significant delay in tmax being seen on co-administration with etoposide and propantheline. The co-administration of ethanol or bile salts (agents that significantly improved the stability of etoposide in artificial intestinal fluid) with oral etoposide similarly had no effect on improving the etoposide AUC or reducing the variability in AUC, suggesting that drug stability in vivo was not affected by these agents. In the third study, the co-administration of cimetidine had no effect on the pharmacokinetics of oral or i.v. etoposide, despite the previous observation that the etoposide stability was markedly improved at pH 3-5 as compared with pH 1 in artificial gastric fluid. This series of studies, designed to investigate factors that improved etoposide stability in lab. studies, failed to demonstrate any potentially useful improvement in AUC or bioavailability in the clin. setting.(b) Shah, J. C.; Chen, J. R.; Chow, D. Preformulation study of etoposide: identification of physicochemical characteristics responsible for the low and erratic oral bioavailability of etoposide. Pharm. Res. 1989, 6, 408– 412, DOI: 10.1023/A:1015935532725[Crossref], [PubMed], [CAS], Google Scholar.74bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1MXkvVeqtL4%253D&md5=2b8afef71712ed9441c2ca02eec6c0baPreformulation study of etoposide: identification of physicochemical characteristics responsible for the low and erratic oral bioavailability of etoposideShah, Jaymin C.; Chen, Jivn R.; Chow, DianaPharmaceutical Research (1989), 6 (5), 408-12CODEN: PHREEB; ISSN:0724-8741.Preformulation studies of etoposide (I), including pH-soly. profile, partition coeff., pH-stability profile, and in vitro dissoln. kinetics, were conducted to identify the responsible factor(s) for the low and erratic oral bioavailability of I. A stability-indicating HPLC assay was used for drug monitoring. The equil. aq. soly. of I at 37° was low, 148.5-167.25 μg/mL, and did not vary over the pH range of 2 to 6. The pH-stability profile indicated rapid degrdn. of I at pH 1.3 and 10, with degrdn. half-lives of 2.88 and 3.83 h, resp., at 25°. The half-life at pH 7.30 was 27.72 days. Max. stability at 25° was reached at pH 5 to 6.15, with half-lives of 63 and 49.5 days, resp. The intrinsic dissoln. rate was slow, 0.0094 mg/min/cm2, while the I partition coeff. between n-octanol and water was 9.94. Therefore, I absorption appears to be dissoln. rate-limited rather than permeation rate-limited. The low equil. aq. soly., slow intrinsic dissoln. rate, and chem. instability at pH 1.3 could account for the low oral bioavailability.(c) Toffoli, G.; Corona, G.; Basso, B.; Boiocchi, M. Pharmacokinetic optimization of treatment with oral etoposide. Clin. Pharmacokinet. 2004, 43, 441– 466, DOI: 10.2165/00003088-200443070-00002[Crossref], [PubMed], [CAS], Google Scholar74chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXltlGjsLw%253D&md5=346f1cb2a0b8c46971b35793c3e16a86Pharmacokinetic optimisation of treatment with oral etoposideToffoli, Giuseppe; Corona, Giuseppe; Basso, Barbara; Boiocchi, MauroClinical Pharmacokinetics (2004), 43 (7), 441-466CODEN: CPKNDH; ISSN:0312-5963. (Adis International Ltd.)A review. Etoposide is a deriv. of podophyllotoxin widely used in the treatment of several neoplasms, including small cell lung cancer, germ cell tumors and non-Hodgkin's lymphomas. Prolonged administration of etoposide aims for continuous inhibition of topoisomerase II, the intracellular target of etoposide, thus preventing tumor cells from repairing DNA breaks. However, the clin. advantages of extended schedules as compared with conventional short-term infusions remain unclear. Oral administration of etoposide represents the most feasible and economic strategy to maintain effective concns. of drug for extended times. Nevertheless, the efficacy of oral etoposide therapy is contingent on circumventing pharmacokinetic limitations, mainly low and variable bioavailability. Inhibition of small bowel and hepatic metab. of etoposide with specific cytochrome P 450 inhibitors or inhibition of the intestinal P-glycoprotein efflux pump have been attempted to increase the bioavailability of oral etoposide, but the best results were obtained with daily oral administration of low etoposide doses (50-100 mg/day for 14-21 days). Saturable absorption of etoposide was reported for doses greater than 200 mg/day, whereas lower doses were assocd. with increased bioavailability, although they were characterized by high inter- and intrapatient variability. Pharmacokinetic parameters such as plasma trough concn. between two oral administrations (C24,trough), drug exposure time above a threshold value and area under the plasma concn.-time curve have been correlated with the pharmacodynamic effect of oral etoposide. Pharmacokinetic-pharmacodynamic relationships indicate that severe toxicity is avoided when peak plasma concns. do not exceed 3-5 mg/L and C24,trough is under the threshold limit of 0.3 mg/L. To maintain effective etoposide plasma concns. during prolonged oral administration, pharmacokinetic variability must be monitored in each patient, taking account of factors from many pharmacokinetic studies of etoposide, including absorption, distribution, protein binding, metab. and elimination. Dosage redn. is generally useful to avoid haematol. toxicity in patients with renal dysfunction (creatinine clearance <50 mL/min). The need for dosage adjustment based on liver function in patients with liver dysfunction is not completely defined, but generally is not indicated in patients with minor liver dysfunction. Adaptive dosage adjustment based on individual pharmacokinetic parameters, estd. using limited sampling strategies and population pharmacokinetic models, is more appropriate. This approach has been used with success in different clin. trials to increase the etoposide dosage, without significantly increasing toxicity. Various pharmacodynamic models have been proposed to guide etoposide oral dosage. However, they lack precision and accuracy and need to be refined by considering other predictor variables in order to extend their application in current clin. practice.
- 75(a) Saulnier, M. G.; Langley, D.; Kadow, J. F.; Senter, P. D.; Knipe, J.; Tun, M. M.; Vyas, D. M.; Doyle, T. W. Synthesis of etoposide phosphate, BMY-40481, a water-soluble clinically active prodrug of etoposide. Bioorg. Med. Chem. Lett. 1994, 4, 2567– 2572, DOI: 10.1016/S0960-894X(01)80285-7[Crossref], [CAS], Google Scholar.75ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXit1Orsrg%253D&md5=f7b1af24686a636b3d76115f14c224b9Synthesis of etoposide phosphate, BMY-40481: a water-soluble clinically active prodrug of etoposideSaulnier, Mark G.; Langley, David R.; Kadow, John F.; Senter, Peter D.; Knipe, Jay O.; Tun, Min Min; Vyas, Dolatrai M.; Doyle, Terrence W.Bioorganic & Medicinal Chemistry Letters (1994), 4 (21), 2567-72CODEN: BMCLE8; ISSN:0960-894X. (Elsevier)Etoposide phosphate (BMY-40481) I (R = PO3H2) is synthesized semi-synthetically from the clin. approved anticancer parent drug, etoposide (VP-16-213) I (R = H), and also from natural (-)-epipodophyllotoxin. Etoposide phosphate functions as a clin. active, water sol. prodrug of etoposide.(b) Chabot, G G; Armand, J P; Terret, C; de Forni, M; Abigerges, D; Winograd, B; Igwemezie, L; Schacter, L; Kaul, S; Ropers, J; Bonnay, M Etoposide bioavailability after oral administration of the prodrug etoposide phosphate in cancer patients during a phase I study. J. Clin. Oncol. 1996, 14, 2020– 2030, DOI: 10.1200/JCO.1996.14.7.2020[Crossref], [PubMed], [CAS], Google Scholar75bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XksFejt74%253D&md5=9c0d38ad2739bd812868ae1c99a82d01Etoposide bioavailability after oral administration of the prodrug etoposide phosphate in cancer patients during a phase I studyChabot, G. G.; Armand, J. -P.; Terref, C.; De Forni, M.; Abigerges, D.; Winograd, B.; Igwemezie, L.; Schacter, L.; Kaul, S.; et al.Journal of Clinical Oncology (1996), 14 (7), 2020-2030CODEN: JCONDN; ISSN:0732-183X. (Saunders)The purpose of this study was to det. the bioavailability (F) of etoposide (E; VP-16) after oral administration of the water-sol. prodrug etoposide phosphate (EP;BMY-40481) during a phase I trial in cancer patients. Patients and Methods: Twenty-nine patients received oral EP (capsules, 50 to 150 mg/M2/d of E equiv.) for 5 days in week 1 course (1), followed every 3 wk there-after by a daily i.v. (IV) infusion for 5 days of E (80 mg/M2, 1-h IV infusion; course (2)); in three patients, the IV E course was given before oral EP. Plasma and urine E pharmacokinetics (high-performance liq. chromatog. [HPLC]) were performed on the first day of oral EP administration and on the first day of IV E. Twenty-six of 29 patients completed two courses or more, whereas three patients received only one course due to toxicity. Myelosuppression was dose-dependent and dose-limiting, with grade 4 leukoneutropenia in four of 15 patients at 125 mg/M2 and in five of seven patients at 150 mg/M2. One patient died of meningeal hemorrhage related to grade 4 thrombocytopenia. Other toxicities were infrequent and/or manageable. No objective response was obsd. The max.-tolerated dose (MTD) is therefore 150 mg/M2, and the recommended oral dose of EP for phase II trials in this poor-risk patient population is 125 mg/M2. Twenty-six patients had pharmacokinetic data for both oral EP and IV E, whereas three had pharmacokinetic data on the IV E course only. After oral administration of EP, the pharmacokinetics of E were as follows: mean absorption rate const. (Ka), 1.7 h-1 (mean); lag time, 0.3 h; time of max. concn. (tmax), 1.6 h; and mean half-lives (t1/2), 1.6 (first) and 10.3 h (terminal); the increase in the area under the plasma concn.-vs.-time curve (AUC) of E was proportional to the EP dose. After the 1-h IV infusion of E, max. concn. (Cmax) was 15 μg/mL; mean AUC, 88.0 μg*h/mL; mean total-body clearance (CL), 0.97 L/h/M2 (16.2 mL/min/M2); and mean t1/2, 0.9 (first) and 8.1 h (terminal). The 24-h urinary excretion of E after IV E was significantly higher (33%) compared with that of oral EP (17%). Significant correlation was obsd. between the neutropenia at nadir and the AUC of E after oral EP administration (r =.58, sigmoid max. effect [Emax] model). The mean F of E after oral administration of EP in 26 patients was 68.0% (coeff. of variation [CV], 26.3%; F range, 35.5% to 111.8%). In this study, tumor type, as well as EP dose, did not significantly influence the F in E. There was no difference in F of E, whether oral EP was administered before or after IV E. Compared with literature data on oral E, the percent F in E after oral prodrug EP administration was 19% higher at either low (≤ 100 mg/M2) or high (> 100 mg/M2) doses. Similarly to E, the main toxicity of the prodrug EP is dose-dependent leukoneutropenia, which is dose-limiting at the oral MTD of 150 mg/M2/d for 5 days. The recommended oral dose of EP is 125 mg/M2/d for 5 days every 3 wk in poor-risk patients. Compared with literature data, oral EP has a 19% higher F value compared with oral E either at low or high doses. This higher F in E from oral prodrug EP appears to be a pharmacol. advantage that could be of potential pharmacodynamic importance for this drug.
- 76(a) Heimbach, T.; Oh, D.-M.; Li, L. Y; Rodrıguez-Hornedo, N.ır; Garcia, G.; Fleisher, D. Enzyme-mediated precipitation of parent drugs from their phosphate prodrugs. Int. J. Pharm. 2003, 261, 81– 92, DOI: 10.1016/S0378-5173(03)00287-4[Crossref], [PubMed], [CAS], Google Scholar.76ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXls1Sqs7o%253D&md5=48f6f7452f36afafa782eabb81936268Enzyme-mediated precipitation of parent drugs from their phosphate prodrugsHeimbach, Tycho; Oh, Doo-Man; Li, Lilian Y.; Rodriguez-Hornedo, Nair; Garcia, George; Fleisher, DavidInternational Journal of Pharmaceutics (2003), 261 (1-2), 81-92CODEN: IJPHDE; ISSN:0378-5173. (Elsevier Science B.V.)Many oral phosphate prodrugs have failed to improve the rate or extent of absorption compared to their insol. parent drugs. Rapid parent drug generation via intestinal alk. phosphatase can result in supersatd. solns., leading to parent drug pptn. The purpose was to (1) investigate whether parent drugs can ppt. from prodrug solns. in presence of alk. phosphatase; (2) det. whether induction times are influenced by (a) dephosphorylation rate, (b) parent drug supersatn. level, and (c) parent drug soly. Induction times were detd. from increases in optical densities after enzyme addn. to prodrug solns. of TAT-59, fosphenytoin and estramustine phosphate. Apparent supersatn. ratios (σ) were calcd. from parent drug soly. at intestinal pH. Pptn. could be generated for all three prodrugs. Induction times decreased with increased enzyme activity and supersatn. level and were within gastrointestinal (GI) residence times for TAT-59 concn.≥21 μM (σ≥210). Induction times for fosphenytoin were less than the GI residence time (199 min) for concns. of approx. 352 μM (σ=4.0). At approx. 475 μM (σ=5.3) the induction times were less than 90 min. For estramustine-phosphate, no pptn. was obsd. within GI residence times. Enzyme-mediated pptn. will depend on apparent supersatn. ratios, parent drug dose, soly. and solubilization by the prodrug.(b) Heimbach, T.; Oh, D. M.; Li, L. Y.; Forsberg, M.; Savolainen, J.; Leppänen, J.; Matsunaga, Y.; Flynn, G.; Fleisher, D. Absorption rate limit considerations for oral phosphate prodrugs. Pharm. Res. 2003, 20, 848– 856, DOI: 10.1023/A:1023827017224[Crossref], [PubMed], [CAS], Google Scholar76bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXjvFyisrg%253D&md5=954bff3aa76b382614901161042f5cd9Absorption Rate Limit Considerations for Oral Phosphate ProdrugsHeimbach, Tycho; Oh, Doo-Man; Li, Lilian Y.; Forsberg, Markus; Savolainen, Jouko; Leppaenen, Jukka; Matsunaga, Yasushi; Flynn, Gordon; Fleisher, DavidPharmaceutical Research (2003), 20 (6), 848-856CODEN: PHREEB; ISSN:0724-8741. (Kluwer Academic/Plenum Publishers)The potential of phosphate ester prodrugs to significantly improve the absorptive flux of poorly sol. parent drugs was evaluated. Absorptive transport studies of parent drugs and their prodrugs were carried out in Caco-2 cells. Prodrugs of parent drugs with variable aq. solubilities were tested: Hydrocortisone-phosphate/Hydrocortisone, Fosphenytoin/phenytoin, TAT-59/DP-TAT-59, and Entacapone phosphate/Entacapone. Addnl. absorption studies were carried out in rats. Absorptive fluxes of DP-TAT-59 and phenytoin increased 9.8 or 3.3-fold after dosing TAT-59 and 500 μM fosphenytoin, resp. Hydrocortisone's flux did not increase with hydrocortisone-phosphate at 100 μM. Permeability of the highly lipophilic and protein bound compd., DP-TAT-59, was significantly increased with serosal albumin. No permeability increase was obsd. for the other drugs with albumin. Entacapone phosphate failed to improve the flux of entacapone compared to an entacapone soln., but the prodrug soln. did yield higher entacapone plasma levels in rats when compared with an entacapone suspension. Ideal phosphate prodrug candidates are characterized by high permeability and low soly. (BCS Class II drugs). For low dose BCS Class II drug candidates, however, no biopharmaceutical advantage may be gained. Phosphate prodrugs of parent drugs with limited permeability may fail. When screening highly lipophilic parent drugs transport studies should be done with albumin.
- 77Long, B. H. Mechanisms of action of teniposide (VM-26) and comparison with etoposide (VP-16). Semin. Oncol. 1992, 19 (Suppl. 6), 3– 19[PubMed], [CAS], Google Scholar77https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK3s%252FjtVyqtw%253D%253D&md5=1d2ac6451a47f7ce371cb2ed7bfa36a2Mechanisms of action of teniposide (VM-26) and comparison with etoposide (VP-16)Long B HSeminars in oncology (1992), 19 (2 Suppl 6), 3-19 ISSN:0093-7754.Teniposide is the result of extensive, long-term efforts to refine and improve on the cytotoxic activity of naturally occurring compounds extracted from podophyllin resins and purified. Isolation of an extremely potent though minor component of one of the early podophyllin derivatives led in turn to the synthesis and evaluation of several aldehyde condensation products. Two of these, teniposide and etoposide, were further investigated when their considerable antitumor activity in animals became apparent. Recognition of transient DNA breaks induced by teniposide, etoposide, and other podophyllotoxin analogues established not only that their site of activity was DNA but also that their cytotoxic effect was dose-dependent. Extensive investigation has further indicated that a primary mechanism of action of these agents involves inhibition of the catalytic activity of eukaryote topoisomerase II and, more important, the consequent stabilization of the normally transient covalent intermediate formed between the DNA substrate and the enzyme. As a result of elevated enzyme levels or enzyme activity, or both, in transformed cells, topoisomerase II inhibitors are highly selective for cancer cells versus normal cells. Although teniposide is not substantially more potent than etoposide in terms of catalytic inhibition or stabilization of the DNA-enzyme intermediate, it is more readily taken up by cells, which results in greater teniposide accumulation within the cells and, thus, a greater capacity for cytotoxicity.
- 78(a) Splinter, T. A.; Holthuis, J. J.; Kok, T. C.; Post, M. H. Absolute bioavailability and pharmacokinetics of oral teniposide. Semin. Oncol. 1992, 19 (Suppl. 6), 28– 34[PubMed], [CAS], Google Scholar.78ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK3s%252FjtVyqtg%253D%253D&md5=764b15a70053192998cb6decc15365a8Absolute bioavailability and pharmacokinetics of oral teniposideSplinter T A; Holthuis J J; Kok T C; Post M HSeminars in oncology (1992), 19 (2 Suppl 6), 28-34 ISSN:0093-7754.The absolute bioavailability and pharmacokinetics of orally administered teniposide were investigated in 25 patients. All patients received 50 to 60 mg/m2 teniposide intravenously on day 1, before oral administration. Six patients received 60 mg/m2 as a single oral dose on day 8; 5 patients received 60 mg/m2 and 120 mg/m2 as a single oral dose on days 8 and 15, respectively; 5 patients received 120 mg/m2 and 240 mg/m2 as a single oral dose on days 8 and 15, respectively; 6 patients received 60 mg/m2 as a single oral dose on 5 consecutive days from days 8 to 12; and 3 patients received 50 mg/m2 three times a day at 6-hour intervals on day 8. The mean absolute bioavailability was 41.6% +/- 14.2% with a large interindividual variability (range, 19.7% to 71.4%) and a low intraindividual variability (range, 2.8% to 13.9%). At a dose of 240 mg/m2, the bioavailability was decreased, whereas administration of multiple doses on 1 day or 5 consecutive days increased the overall bioavailability. In conclusion, teniposide can be administered orally with a bioavailability comparable with that of etoposide. The schedule dependency of both drugs warrants investigations of oral administration for 21 or more days. A formulation of teniposide capsules of 50 mg or less would be most helpful to facilitate oral administration.(b) Relling, M. V.; Evans, R.; Dass, C.; Desiderio, D. M.; Nemec, J. Human cytochrome P450 metabolism of teniposide and etoposide. J. Pharmacol. Exp. Ther. 1992, 261, 491– 496[PubMed], [CAS], Google Scholar78bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK38XktF2rsb8%253D&md5=21596e6fc82edd14fed6c600d15cfe8fHuman cytochrome P450 metabolism of teniposide and etoposideRelling, Mary V.; Evans, Robert; Dass, Chhabil; Desiderio, Dominic M.; Nemec, JosefJournal of Pharmacology and Experimental Therapeutics (1992), 261 (2), 491-6CODEN: JPETAB; ISSN:0022-3565.Although teniposide (VM26) and etoposide (VP16) are eliminated mostly by nonrenal mechanisms, their cytochrome P 450 metab. in humans has not been reported. The objective of this study was to det. the affinity and capacity of P 450 O-demethylation of VM26 and VP16 in a variety of human livers. Formation of catechols of VM26 and VP16 was detected in 24 and 26 of 26 liver microsomal prepns., resp., with wide variability in max. catechol formation rates from VM26 (41-fold) and VP16 (30-fold range), even among normal livers. Maximal activity measurements at 500 μM substrate were lower for VM26 catechol formation (mean = 1.5 nmol/mg/h) than for VP16 catechol (mean = 3.2 nmol/mg/h) in 26 livers. Maximal activities for VP16 and VM26 O-demethylation, and ethoxycoumarin O-deethylation were significantly higher in normal than in diseased livers. No differences were found in activities related to age, sex or race of the liver donor. In all five livers tested over a range of substrate concns., Km (19.7, 23.2, 43.5, 30.1 and 22.0 μM) and Vmax values (1.0, 1.2, 4.4, 8.2 and 4.0 nmol/mg/h) for VM26 were lower compared to values for VP16 (Km - 60.2, 115.1, 87.3, 42.1 and 81.9 μM; Vmax = 1.4, 3.3, 10.3, 27.5 and 10.1 nmol/mg/h). Despite higher VP16 catechol formation, VM26 underwent greater overall reduced NADP-dependent metab. than VP16, consistent with greater nonrenal clearance of VM26 in vivo. In addn. to the role of O-demethylation as a route of catabolism for VM26 and VP16 in humans, the significant variability in formation of the reactive catechol metabolites may play a role in their clin. efficacy and toxicity.
- 79Jacob, D. A.; Mercer, S. L.; Osheroff, N.; Deweese, J. E. Etoposide quinone is a redox-dependent topoisomerase II poison. Biochemistry 2011, 50, 5660– 5667, DOI: 10.1021/bi200438m[ACS Full Text], [CAS], Google Scholar79https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXmvFSlt70%253D&md5=f2314e9bb986d49398b568690295ea6eEtoposide Quinone Is a Redox-Dependent Topoisomerase II PoisonJacob, David A.; Mercer, Susan L.; Osheroff, Neil; Deweese, Joseph E.Biochemistry (2011), 50 (25), 5660-5667CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)Etoposide is a topoisomerase II poison that is used to treat a variety of human cancers. Unfortunately, 2-3% of patients treated with etoposide develop treatment-related leukemias characterized by 11q23 chromosomal rearrangements. The mol. basis for etoposide-induced leukemogenesis is not understood but is assocd. with enzyme-mediated DNA cleavage. Etoposide is metabolized by CYP3A4 to etoposide catechol, which can be further oxidized to etoposide quinone. A CYP3A4 variant is assocd. with a lower risk of etoposide-related leukemias, suggesting that etoposide metabolites may be involved in leukemogenesis. Although etoposide acts at the enzyme-DNA interface, several quinones poison topoisomerase II via redox-dependent protein adduction. The effects of etoposide quinone on topoisomerase IIα-mediated DNA cleavage have been examd. previously. Although findings suggest that the activity of the quinone is slightly greater than that of etoposide, these studies were carried out in the presence of significant levels of reducing agents (which should reduce etoposide quinone to the catechol). Therefore, the authors examd. the ability of etoposide quinone to poison human topoisomerase IIα in the absence of reducing agents. Under these conditions, etoposide quinone was ∼5-fold more active than etoposide at inducing enzyme-mediated DNA cleavage. Consistent with other redox-dependent poisons, etoposide quinone inactivated topoisomerase IIα when incubated with the protein prior to DNA and lost activity in the presence of dithiothreitol. Unlike etoposide, the quinone metabolite did not require ATP for maximal activity and induced a high ratio of double-stranded DNA breaks. The authors' results support the hypothesis that etoposide quinone contributes to etoposide-related leukemogenesis.
- 80Yang, J.; Bogni, A.; Schuetz, E. G.; Ratain, M.; Dolan, M. E.; McLeod, H.; Gong, L.; Thorn, C.; Relling, M. V.; Klein, T. E.; Altman, R. B. Etoposide pathway. Pharmacogenet. Genomics 2009, 19, 552– 553, DOI: 10.1097/FPC.0b013e32832e0e7f[Crossref], [PubMed], [CAS], Google Scholar80https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXntlOhtrs%253D&md5=f7837171ab20246dfa0b962787ade0edEtoposide pathwayYang, Jun; Bogni, Alessia; Schuetz, Erin G.; Ratain, Mark; Eileen Dolan, M.; McLeod, Howard; Gong, Li; Thorn, Caroline; Relling, Mary V.; Klein, Teri E.; Altman, Russ B.Pharmacogenetics and Genomics (2009), 19 (7), 552-553CODEN: PGHEAI; ISSN:1744-6872. (Lippincott Williams & Wilkins)A review. Antitumor etoposide effects and disposition are summarized.
- 81Pui, C. H.; Ribeiro, R. C.; Hancock, M. L.; Rivera, G. K.; Evans, W.; Raimondi, S. C.; Head, D. R.; Behm, F. G.; Mahmoud, M. H.; Sandlund, J. T.; Crist, W. M. Acute myeloid leukemia in children treated with epipodophyllotoxins for acute lymphoblastic leukemia. N. Engl. J. Med. 1991, 325, 1682– 1687, DOI: 10.1056/NEJM199112123252402[Crossref], [PubMed], [CAS], Google Scholar81https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK38%252FkvFKiuw%253D%253D&md5=9610ef0c41b7933f571f40bc0aedf074Acute myeloid leukemia in children treated with epipodophyllotoxins for acute lymphoblastic leukemiaPui C H; Ribeiro R C; Hancock M L; Rivera G K; Evans W E; Raimondi S C; Head D R; Behm F G; Mahmoud M H; Sandlund J TThe New England journal of medicine (1991), 325 (24), 1682-7 ISSN:0028-4793.BACKGROUND AND METHODS: Treatment of cancer with the epipodophyllotoxins (etoposide and teniposide) has been linked to the development of acute myeloid leukemia (AML) in children and adults, but the factors that might influence the risk of this complication of therapy are poorly defined. We therefore assessed the importance of potential risk factors for secondary AML in 734 consecutive children with acute lymphoblastic leukemia who attained complete remission and received continuation (maintenance) treatment according to different schedules of epipodophyllotoxin administration. RESULTS: Secondary AML was diagnosed in 21 of the 734 patients, in 17 of whom this complication was the initial adverse event. Prolonged administration of epipodophyllotoxin (teniposide with or without etoposide) twice weekly or weekly was independently associated with the development of secondary AML (P less than 0.01 by Cox regression analysis). The overall cumulative risk of AML at six years was 3.8 percent (95 percent confidence interval, 2.3 percent to 6.1 percent); but within the subgroups treated twice weekly or weekly, the risks were 12.3 percent (95 percent confidence interval, 5.7 percent to 25.4 percent) and 12.4 percent (95 percent confidence interval, 6.1 percent to 24.4 percent), respectively. In the subgroups not treated with epipodophyllotoxins or treated with them only during remission induction or every two weeks during continuation treatment, the highest cumulative risk was 1.6 percent (95 percent confidence interval, 0.4 percent to 6.1 percent). After adjustment for treatment frequency, there was no apparent relation between the total dose of epipodophyllotoxins and the development of secondary AML. The relative hazard of etoposide as compared with teniposide could not be determined. CONCLUSIONS: The risk of epipodophyllotoxin-related AML depends largely on the schedule of drug administration. Other factors, including the cumulative dose of epipodophyllotoxin, radiotherapy, and the initial biologic features of the leukemic blast cells, do not appear to have critical roles.
- 82Ashton, M. J.; Lawrence, C.; Karlsson, J.; Stuttle, K. A.; Newton, C. G.; Vacher, B. Y.; Webber, S.; Withnall, M. J. Anti-inflammatory 17β-thioalkyl-16α,17α-ketal and -acetal androstanes: a new class of airway selective steroids for the treatment of asthma. J. Med. Chem. 1996, 39, 4888– 4896, DOI: 10.1021/jm9604639[ACS Full Text], [CAS], Google Scholar82https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XmvVWnsbw%253D&md5=bbf0a7782e09994e5a55b4cba011520cAnti-inflammatory 17β-Thioalkyl-16α,17α-ketal and -acetal Androstanes: A New Class of Airway Selective Steroids for the Treatment of AsthmaAshton, Michael J.; Lawrence, Christopher; Karlsson, Jan-Anders; Stuttle, Keith A. J.; Newton, Christopher G.; Vacher, Bernard Y. J.; Webber, Stephen; Withnall, Michael J.Journal of Medicinal Chemistry (1996), 39 (25), 4888-4896CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The synthesis and anti-inflammatory potencies of a new class of 17β-thioalkyl-16α,17α-ketal and -acetal androstanes, e.g. I [R1 - R3 = Me, X = H, F; R1 = H, R2 = Pr, R3 = Me, X = H, F; R1 = X = H, R2 = Pr, R3 = Et, CHMe2; R1 = X = H, R2 = (E)-CH:CHMe, R3 = Me], are described. This new class of steroids was made by fragmentation of 2-thioxo-1,2-dihydropyrid-1-yl esters of the corresponding 17-acids to the 17-radical. The radical generated was trapped using a variety of radicophilic disulfides, giving a steroidal D-ring having acetal or ketal functionality at C-16 and C-17, together with a sulfide link at C-17. Compds. from this series bind to the glucocorticoid receptor with high potency and are functional agonists as measured by their ability to induce tyrosine aminotransferase activity in a rat hepatic cell line in vitro. These 17β-thioalkyl androstanes potently inhibit Sephadex-induced rat lung inflammation when administered directly into the airways. The high topical potency, together with a low propensity to induce systemic glucocorticoid-like side effects (rat thymus involution), provides the present compds. with a high degree of airway selectivity compared with currently available inhaled glucocorticoids. The presently described 17β-thioalkyl-16α,17α-ketal androstanes may be useful for therapies for inflammatory diseases such as asthma.
- 83(a) Gupta, R.; Jindal, D. P.; Kumar, G. Corticosteroids: the mainstay in asthma therapy. Bioorg. Med. Chem. 2004, 12, 6331– 6342, DOI: 10.1016/j.bmc.2004.05.045[Crossref], [PubMed], [CAS], Google Scholar.83ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhtVSnsr3M&md5=6c47f83d5ce6a033a15ba096ef336ba5Corticosteroids: the mainstay in asthma therapyGupta, Ranju; Jindal, Dharam Paul; Kumar, GulshanBioorganic & Medicinal Chemistry (2004), 12 (24), 6331-6342CODEN: BMECEP; ISSN:0968-0896. (Elsevier Ltd.)A review. Inflammation is now marked as a central feature of asthma pathophysiol. and aims of current asthma management are not only to treat acute symptoms of wheezing, breathlessness, chest tightness, cough but also to suppress the underlying inflammatory component. Despite the availability of a no. of drugs, corticosteroids remain the mainstay in the management of all types of asthma as these are the most potent and effective antiinflammatory agents available so far. Corticosteroids suppress virtually every step in inflammation. However therapeutic doses of oral glucocorticoids are assocd. with a range of adverse reactions. To overcome these side effects, inhalations have been developed to deliver glucocorticoids directly to the lungs and in the process a no. of aerosol prepns. have become available, which have advantage of significantly lower toxicity due to low systemic absorption from the respiratory tract and rapid inactivation. Despite considerable efforts by pharmaceutical industry, it has been difficult to develop novel therapeutic agents for asthma management, which could surpass inhaled corticosteroids. Currently the data favors using inhaled corticosteroids as monotherapy in the majority of patients in all kinds of asthma. If combination therapy is recommended to achieve addnl. control in severe asthma cases, other drugs such as β-agonists, antileukotrienes, theophylline, etc. are considered as adjunct therapies to corticosteroids. This review discusses the importance of corticosteroids as first line therapy for asthma treatment with the availability of inhaled corticosteroids for chronic treatment and oral formulations for treating acute exacerbations of moderate to severe asthma.(b) Ye, Q.; He, X.; D’Urzo, A. A review on the safety and efficacy of inhaled corticosteroids in the management of asthma. Pulmon. Ther. 2017, 3, 1– 18, DOI: 10.1007/s41030-017-0043-5
- 84Edsbäcker, S.; Andersson, P.; Lindberg, C.; Ryrfeldt, A.; Thalén, A. Metabolic acetal splitting of budesonide. A novel inactivation pathway for topical glucocorticoids. Drug Metab. Dispos. 1987, 15, 412– 417[PubMed], [CAS], Google Scholar84https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL2s3nsFCitg%253D%253D&md5=fa1c2afa97713d477501709b6fef4ecaMetabolic acetal splitting of budesonide. A novel inactivation pathway for topical glucocorticoidsEdsbacker S; Andersson P; Lindberg C; Ryrfeldt A; Thalen ADrug metabolism and disposition: the biological fate of chemicals (1987), 15 (3), 412-7 ISSN:0090-9556.Topical glucocorticoids usually have a high intrinsic glucocorticoid potency and may, after systemic uptake, induce side effects. The systemic inactivation of budesonide is rapid due to extensive liver biotransformation. The major metabolic pathway, 16 alpha, 17 alpha-acetal splitting, is unique for budesonide within this group of compounds. This biotransformation is catalyzed by microsomal monooxygenases and proceeds via hydroxylation and subsequent rearrangement to an intermediary ester. The ester is cleaved by hydrolysis to 16 alpha-hydroxyprednisolone and butyric acid. The hydrolysis product 16 alpha-hydroxyprednisolone has strongly reduced glucocorticoid activity.
- 85Spencer, C. M.; McTavish, D. A review of its pharmacological properties and therapeutic efficacy in inflammatory bowel disease. Drugs 1995, 50, 854– 872, DOI: 10.2165/00003495-199550050-00006[Crossref], [PubMed], [CAS], Google Scholar85https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28Xit12ntA%253D%253D&md5=ad52e162d2c723429dad116abcb9f233Budesonide: A review of its pharmacological properties and therapeutic efficacy in inflammatory bowel diseaseSpencer, Caroline M.; McTavish, DonnaDrugs (1995), 50 (5), 854-72CODEN: DRUGAY; ISSN:0012-6667. (Adis)A review with 51 refs. Budesonide is a glucocorticoid with high topical activity, but low systemic bioavailability which results in reduced systemic effects in comparison with other glucocorticoids. To date, it has been evaluated for use in patients with inflammatory bowel disease when administered either orally as a controlled ileal release formulation or rectally as an enema. In comparative trials, daily treatment with budesonide enema 2 mg/100mL for 4 wk produced endoscopic remission or improvement in 46 to 84% of patients with active distal ulcerative colitis and/or proctitis and histol. remission or improvement in 45 to 68%. In general, this regimen was a effective as regimens of hydrocortisone, methylprednisolone, prednisolone or mesalazine (5-amino-salicylic acid, mesalamine) enemas, but caused less suppression of plasma cortisol levels than the other glucocorticoids. Oral treatment with controlled release budesonide 9 mg/day for 8 wk produces clin. remission in 42 to 67% of patients with active Crohn's disease of the ileum, ileocecal region and/or ascending colon and significantly reduces Crohn's disease activity index scores compared with baseline and placebo. Results of a quality-of-life questionnaire reflected these clin. improvements. Budesonide has similar efficacy to prednisolone. Response to budesonide is maintained after dosage tapering at 8 wk. Compared with placebo, maintenance treatment with oral budesonide 3 or 6 mg/day increases the duration of remission in patients with Crohn's disease, but does not appear to affect the 1-yr relapse rate. Thus, budesonide, administered rectally to patients with distal ulcerative colitis or proctitis or orally to patients with Crohn's disease of the ileum, ileocecal region and/or ascending colon, is a favorable option for the treatment of acute exacerbations of inflammatory bowel disease. Because of the low incidence of adverse glucocorticoid-related effects assocd. with oral budesonide, it may also be a useful agent for longer term maintenance therapy if further clin. trials confirm its efficacy in this indication.
- 86de Weger, V. A.; Beijnen, J. H.; Schellens, J. H. M. Cellular and clinical pharmacology of the taxanes docetaxel and paclitaxel - a review. Anti-Cancer Drugs 2014, 25, 488– 494, DOI: 10.1097/CAD.0000000000000093[Crossref], [PubMed], [CAS], Google Scholar86https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXls1Glt7c%253D&md5=0e4cf76a8c1762913aeec74c616d6870Cellular and clinical pharmacology of the taxanes docetaxel and paclitaxel - a reviewde Weger, Vincent A.; Beijnen, Jos H.; Schellens, Jan H. M.Anti-Cancer Drugs (2014), 25 (5), 488-494CODEN: ANTDEV; ISSN:0959-4973. (Lippincott Williams & Wilkins)A review. Paclitaxel and docetaxel are active against a range of human cancers. Their antitumor activity is based on stabilization of the microtubule dynamics and thereby disruption of the cell cycle. The taxanes are administered as i.v. solns. in a short administration schedule. Distribution of both taxanes is rapid, with large vols. of distribution and significant binding to plasma proteins. The metab. of paclitaxel is mediated primarily by the P 450 cytochrome enzymes CYP2C8 and CYP3A, whereas docetaxel is only metabolized by CYP3A4. The most common toxicities after i.v. administration are neutropenia, hypersensitivity reactions, neurotoxicity, and alopecia. Several new administration forms are in development; albumin-bound paclitaxel (Abraxane) has recently been registered. Oral formulations of taxanes have been developed, and several are now undergoing phase I trials. New formulations might improve efficacy and safety and could be easier to use.
- 87(a) Yassine, F.; Salibi, E.; Gali-Muhtasib, H. Overview of the formulations and analogues in the taxanes&. story. Curr. Med. Chem. 2016, 23, 4540– 4558, DOI: 10.2174/0929867323666160907124013[Crossref], [PubMed], [CAS], Google Scholar.87ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXjs1eluw%253D%253D&md5=7028bbbdcb2e83c90b0ccf822922687cOverview of the Formulations and Analogs in the Taxanes'; StoryYassine, Farah; Salibi, Elia; Gali-Muhtasib, HalaCurrent Medicinal Chemistry (2016), 23 (40), 4540-4558CODEN: CMCHE7; ISSN:0929-8673. (Bentham Science Publishers Ltd.)Taxanes are a family of diterpenes produced by the yews (Taxus genus) that are extensively used in chemotherapy. The family encompasses paclitaxel, docetaxel and the recently added cabazitaxel, all of which were proven to be promising anti-cancer drugs. Due to the over harvesting danger threatening the yew trees as well as the many challenges faced by taxane-based chemotherapy, new formulations, analogs and delivery systems are required. Here, we undertook a structured search of the bibliog. database PubMed for peer reviewed research papers relying on key words and date of publication and organized the information based on the method of taxane drug delivery. Papers retrieved were from journals with significant impact and comparable scope. A total of 126 papers were reviewed, 81 of which published work related to the taxane formulations and nanoparticles, and 22 focused on the analogs derived from the three taxanes. Although recent articles investigate the effectiveness of taxane formulations, most of these formulations are still at the pre-clin. level. However, many of the taxane analogs are currently in clin. trials as second line treatment of aggressive cancers or are used in combination with other chemotherapeutic drugs. The findings corroborate the importance of developing new drug delivery strategies and taxane analogs to improve the efficacy of currently used chemotherapeutic drugs. This finding is further supported by the FDA-approved formulation of paclitaxel that eliminates the need for toxic solvents for drug administration, and the docetaxel analog cabazitaxel which has decreased affinity for efflux pumps.(b) Yared, J. A.; Tkaczuk, K. H. R. Update on taxane development: new analogues and new formulations. Drug Des., Dev. Ther. 2012, 6, 371– 384, DOI: 10.2147/DDDT.S28997[Crossref], [PubMed], [CAS], Google Scholar.87bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvFSlu7vI&md5=e43b35c36438e05fe2763bd3e2162a24Update on taxane development: new analogs and new formulationsYared, Jean A.; Tkaczuk, Katherine H. R.Drug Design, Development and Therapy (2012), 6 (), 371-384CODEN: DDDTAQ; ISSN:1177-8881. (Dove Medical Press Ltd.)A review. The taxanes (paclitaxel and docetaxel) represent an important class of antineoplastic agents that interfere with microtubule function leading to altered mitosis and cellular death. Paclitaxel (Taxol) was originally extd. from a yew tree (Taxus spp., Taxaceae) a small slow-growing evergreen, coniferous tree. Due to the initial scarcity of paclitaxel, docetaxel (Taxotere) a semisynthetic analog of paclitaxel produced from the needles of European yew tree, Taxus baccata was developed. Docetaxel differs from paclitaxel in two positions in its chem. structure and this small alteration makes it more water sol. Today, paclitaxel and docetaxel are widely prescribed antineoplastic agents for a broad range of malignancies including lung cancer, breast cancer, prostate cancer, Kaposi's sarcoma, squamous cell carcinoma of the head and neck, gastric cancer, esophageal cancer, bladder cancer, and other carcinomas. Although very active clin., paclitaxel and docetaxel have several clin. problems including poor drug soly., serious dose-limiting toxicities such as myelosuppression, peripheral sensory neuropathy, allergic reactions, and eventual development of drug resistance. A no. of these side effects have been assocd. with the solvents used for diln. of these antineoplastic agents: Cremophor EL for paclitaxel and polysorbate 80 for docetaxel. In addn., reports have linked these solvents to the alterations in paclitaxel and docetaxel pharmacokinetic profiles. In this review, we provide preclin. and clin. data on several novel taxanes formulations and analogs which are currently US Food and Drug Administration (FDA)-approved or in clin. development in various solid tumor malignancies. Of the new taxanes nab-paclitaxel and cabazitaxel have enjoyed clin. success and are FDA-approved; while many of the other compds. described in this review are unlikely to be further developed for clin. use in daily practice. Furthermore, the successful clin. emergence of novel nontaxane microtubule-targeting chemotherapy agents such as epothilones and eribulin is liable to further restrict the development of novel taxanes.(c) Baker, A. F.; Dorr, R. T. Drug interactions with the taxanes: clinical implications. Cancer Treat. Rev. 2001, 27, 221– 233, DOI: 10.1053/ctrv.2001.0228[Crossref], [PubMed], [CAS], Google Scholar87chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXnt1SktLo%253D&md5=b374723b96807c5c10862a7a20cb0eb7Drug interactions with the taxanes: Clinical implicationsBaker, A. F.; Dorr, R. T.Cancer Treatment Reviews (2001), 27 (4), 221-233CODEN: CTREDJ; ISSN:0305-7372. (W. B. Saunders)A review. The taxanes paclitaxel and docetaxel are among the most active antitumor agents. Clin. important pharmacodynamic interactions have been reported to occur with these agents that are sequence or schedule dependent. Because the taxanes undergo hepatic oxidn. via the cytochrome P 450 system, pharmacokinetic interactions due to enzyme induction or inhibition can also occur. A comprehensive literature search was conducted using Medline to identify clin. important drug-interactions with the taxanes. Clin. significant taxane interactions were identified for carboplatin, cisplatin, doxorubicin, docetaxel, epirubicin and anticonvulsants. Doxorubicin and epirubicin should be administered 24h before paclitaxel, and the cumulative anthracycline dose limited to 360 mg/m2. This will prevent the enhanced toxicities due to sequence and schedule dependent interactions between anthracyclines and paclitaxel. Conversely, paclitaxel should be administered at least 24h before cisplatin to avoid a decrease in clearance and increase in myelosuppression. With concurrent anticonvulsant therapy, cytochrome P 450 enzyme induction results in decreased paclitaxel plasma steady state concns., possibly requiring an increased dose of paclitaxel. A no. of other drug interactions have been reported in preliminary studies for which clin. significance has yet to be established. Clin. significant drug interactions have been reported to occur when paclitaxel is administered with doxorubicin, cisplatin, or anticonvulsants (phenytoin, carbamazepine, and phenobarbital).
- 88(a) Ishiyama, T.; Iimura, S.; Ohsuki, S.; Uoto, K.; Terasawa, H.; Soga, T. New highly active taxoids from 9β-dihydrobaccatin-9,10-acetals. Bioorg. Med. Chem. Lett. 2002, 12, 1083– 1086, DOI: 10.1016/S0960-894X(02)00069-0[Crossref], [PubMed], [CAS], Google Scholar.88ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XitFWhsbk%253D&md5=7c8653a32138e78497e0ef269fec81d6New highly active taxoids from 9β-Dihydrobaccatin-9,10-acetalsIshiyama, Takashi; Iimura, Shin; Ohsuki, Satoru; Uoto, Kouichi; Terasawa, Hirofumi; Soga, TsunehikoBioorganic & Medicinal Chemistry Letters (2002), 12 (7), 1083-1086CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)To synthesize new highly active taxoids, we designed and synthesized 9β-dihydro-9,10-acetal taxoids. In vitro study of these analogs, e.g. (I), clearly showed them to be more potent than docetaxel.(b) Ishiyama, T.; Iimura, S.; Yoshino, T.; Chiba, J.; Uoto, K.; Terasawa, H.; Soga, T. New highly active taxoids from 9β-dihydrobaccatin-9,10-acetals. Part 2. Bioorg. Med. Chem. Lett. 2002, 12, 2815– 2819, DOI: 10.1016/S0960-894X(02)00628-5[Crossref], [PubMed], [CAS], Google Scholar.88bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38Xntlansrc%253D&md5=1988e89f47dc19cb3ba4bcd3deb6897aNew highly active taxoids from 9β-dihydrobaccatin-9,10-acetals. Part 2Ishiyama, Takashi; Iimura, Shin; Yoshino, Toshiharu; Chiba, Jun; Uoto, Kouichi; Terasawa, Hirofumi; Soga, TsunehikoBioorganic & Medicinal Chemistry Letters (2002), 12 (20), 2815-2819CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)To investigate structure-activity relationships of the 9,10-acetal-9β-dihydro taxoids, we modified the 7-hydroxyl groups of the 9,10-acetonide-3'-(4-pyridyl) analog to deoxy, methoxy, α-F, and 7β,8β-methano group. As a result of this study, the 7-deoxy analog was found to be the strongest among these analogs. In addn., the 7-deoxy-3'-(4-pyridyl) and 7-deoxy-3'-(2-pyridyl) analogs showed stronger activity against cell lines expressing P-glycoprotein than the corresponding 3'-Ph analog.(c) Takeda, Y.; Yoshino, T.; Uoto, K.; Chiba, J.; Ishiyama, T.; Iwahana, M.; Jimbo, T.; Tanaka, N.; Terasawa, H.; Soga, T. New highly active taxoids from 9β-dihydrobaccatin-9,10-acetals. Part 3. Bioorg. Med. Chem. Lett. 2003, 13, 185– 190, DOI: 10.1016/S0960-894X(02)00891-0[Crossref], [PubMed], [CAS], Google Scholar.88chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XpsVels7s%253D&md5=a6f14a4695cb5dec9ece549610bcf5e5New highly active taxoids from 9β-dihydrobaccatin-9,10-acetals. Part 3Takeda, Yasuyuki; Yoshino, Toshiharu; Uoto, Kouichi; Chiba, Jun; Ishiyama, Takashi; Iwahana, Michio; Jimbo, Takeshi; Tanaka, Noriko; Terasawa, Hirofumi; Soga, TsunehikoBioorganic & Medicinal Chemistry Letters (2003), 13 (2), 185-190CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)We synthesized novel water-sol. and orally active taxane analogs, 7-deoxy-9β-dihydro-9,10-O-acetal taxanes. Cytotoxicities of the synthetic compds. were greater than those of paclitaxel and docetaxel, esp. against resistant cancer cell lines expressing P-glycoprotein. In addn., some compds., e.g. I, showed potent antitumor effects against B16 melanoma BL6 in vivo by both iv and po administration.(d) Takeda, Y.; Uoto, K.; Iwahana, M.; Jimbo, T.; Nagata, M.; Atsumi, R.; Ono, C.; Tanaka, N.; Terasawa, H.; Soga, T. New highly active taxoids from 9β-dihydrobaccatin-9,10-acetals. Part 5. Bioorg. Med. Chem. Lett. 2004, 14, 3209– 3215, DOI: 10.1016/j.bmcl.2004.03.109[Crossref], [PubMed], [CAS], Google Scholar.88dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXktVert7w%253D&md5=101061b2722bc9783756ba7761b5df69New highly active taxoids from 9β-dihydrobaccatin-9,10-acetals. Part 5Takeda, Yasuyuki; Uoto, Kouichi; Iwahana, Michio; Jimbo, Takeshi; Nagata, Motoko; Atsumi, Ryo; Ono, Chiho; Tanaka, Noriko; Terasawa, Hirofumi; Soga, TsunehikoBioorganic & Medicinal Chemistry Letters (2004), 14 (12), 3209-3215CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science B.V.)To improve the metabolic stability of I, which exhibited both in vitro antitumor activity and in vivo efficacy by both iv and po administration, we designed and synthesized new taxane analogs. Most of the synthetic compds. maintained excellent antitumor activity and were scarcely metabolized by human liver microsomes. And some compds. exhibited potent antitumor effects against B16 melanoma BL6 in vivo by both iv and po administration similarly to I.(e) Takeda, Y.; Uoto, K.; Chiba, J.; Horiuchi, T.; Iwahana, M.; Atsumi, R.; Ono, C.; Terasawa, H.; Soga, T. New highly active taxoids from 9β-dihydrobaccatin-9,10-acetals. Part 4. Bioorg. Med. Chem. 2003, 11, 4431– 4447, DOI: 10.1016/S0968-0896(03)00454-1[Crossref], [PubMed], [CAS], Google Scholar.88ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXnt1yis74%253D&md5=8e3712c84b388a750d9b52f51791ef59New highly active taxoids from 9β-Dihydrobaccatin-9,10-acetals. Part 4Takeda, Yasuyuki; Uoto, Kouichi; Chiba, Jun; Horiuchi, Takao; Iwahana, Michio; Atsumi, Ryo; Ono, Chiho; Terasawa, Hirofumi; Soga, TsunehikoBioorganic & Medicinal Chemistry (2003), 11 (20), 4431-4447CODEN: BMECEP; ISSN:0968-0896. (Elsevier Science Ltd.)It was shown that a new taxane analog I (R = H), which exhibited both in vitro antitumor activity and in vivo efficacy by both iv and po administration, was prone to be metabolized by human liver microsomes. We identified a major metabolite, M-1, generated by human liver microsomes as I (R = OH), a hydroxylated compd. at the pyridine ring of I (R = H). To improve the metabolic stability of I (R = H) , we designed and synthesized new taxane analogs, I (R = Me, Et, Cl, F, CF3, OMe) based on the structure of M-1, and obtained some compds. that maintained excellent antitumor activity and were scarcely metabolized by human liver microsomes.(f) Shionoya, M.; Jimbo, T.; Kitagawa, M.; Soga, T.; Tohgo, A. DJ-927, a novel oral taxane, overcomes P-glycoprotein-mediated multidrug resistance in vitro and in vivo. Cancer Sci. 2003, 94, 459– 466, DOI: 10.1111/j.1349-7006.2003.tb01465.x[Crossref], [PubMed], [CAS], Google Scholar.88fhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXls1WrtLY%253D&md5=c602b630e10e65548b9d00f326c020e6DJ-927, a novel oral taxane, overcomes P-glycoprotein-mediated multidrug resistance in vitro and in vivoShionoya, Motoko; Jimbo, Takeshi; Kitagawa, Mayumi; Soga, Tsunehiko; Tohgo, AkikoCancer Science (2003), 94 (5), 459-466CODEN: CSACCM; ISSN:1347-9032. (Japanese Cancer Association)DJ-927 is a novel taxane, which was selected for high soly., non-neurotoxicity, oral bioavailability, and potent antitumor activity. In this study, we compared the in vitro and in vivo efficacy of DJ-927 with those of paclitaxel and docetaxel. DJ-927 exhibited stronger cytotoxicity than paclitaxel and docetaxel in various tumor cell lines, esp. against P-glycoprotein (P-gp)-expressing cells. The cytotoxicity of DJ-927, unlike those of other taxanes, was not affected by the P-gp expression level in tumor cells, or by the co-presence of a P-gp modulator. When intracellular accumulation of the three compds. was compared, intracellular amts. of DJ-927 were much higher than those of paclitaxel or docetaxel, particularly in P-gp-pos. cells. In vivo, DJ-927 showed potent antitumor effects against two human solid tumors in male BALB/c-nu/nu mice, and yielded significant life-prolongation in a murine liver metastasis model with male C57BL/6 mice, in which neither paclitaxel nor docetaxel was effective. The results demonstrate the superior efficacy of orally administered DJ-927 over i.v. administered paclitaxel or docetaxel against P-gp-expressing tumors, probably due to higher intracellular accumulation. A phase I clin. trials of DJ-927 is currently ongoing in the US.(g) Ono, C.; Takao, A.; Atsumi, R. Absorption, distribution, and excretion of DJ-927, a novel orally effective taxane, in mice, dogs, and monkeys. Biol. Pharm. Bull. 2004, 27, 345– 351, DOI: 10.1248/bpb.27.345[Crossref], [PubMed], [CAS], Google Scholar.88ghttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXis1aluro%253D&md5=9f794b1d9eb68b4c85106dc589990ec1Absorption, distribution, and excretion of DJ-927, a novel orally effective taxane, in mice, dogs, and monkeysOno, Chiho; Takao, Atsushi; Atsumi, RyoBiological & Pharmaceutical Bulletin (2004), 27 (3), 345-351CODEN: BPBLEO; ISSN:0918-6158. (Pharmaceutical Society of Japan)DJ-927, currently undergoing Phase I clin. trial, is a new orally effective taxane with potent antitumor effects. The absorption, tissue distribution, and excretion of DJ-927 were investigated in mice, dogs, and monkeys after a single oral administration. After oral administration of [14C]DJ-927, radioactivity was rapidly absorbed, with the Cmax occurring within 1-2 h in all species. The blood and plasma radioactivity elimination was biphasic and species-dependent. Elimination half-life of plasma in dogs was much longer than those in monkeys or mice. In mice, radioactivity was rapidly distributed to all tissues except for the central nervous system, esp. to adrenal glands, liver, pituitary glands, kidneys, lungs, and spleen. In all species, radioactivity was mainly excreted in feces. Following a single oral administration to mice, more than 80% of the radioactivity was excreted within 48 h; in dogs and monkeys, 80% of the radioactivity was excreted within 168 h. Urinary excretion was less than 7% of radioactive dose in all species. In vitro plasma protein binding of [14C]DJ-927 in the mouse, dog, and monkey plasma ranged from 92-98%. These studies showed that, the novel oral taxane DJ-927 was rapidly absorbed in all three species when administered by the oral route. The long biol. half-life and slow elimination of radioactivity were distinctive in particular, compared with com. taxanes. DJ-927 (as parent compd. and its metabolites) is widely distributed to tissues except the brain. These preclin. data are useful for the design of clin. trials of DJ-927 and also for their interpretation.(h) Roche, M.; Kyriakou, H.; Seiden, M. Drug evaluation: tesetaxel - an oral semisynthetic taxane derivative. Curr. Opin. Investig. Drugs 2006, 7, 1092– 1099[CAS], Google Scholar.88hhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXntF2nug%253D%253D&md5=b14abcfadad23ba0278835891741da79Drug evaluation: tesetaxel - an oral semisynthetic taxane derivativeRoche, Maria; Kyriakou, Helena; Seiden, MichaelCurrent Opinion in Investigational Drugs (Thomson Scientific) (2006), 7 (12), 1092-1099CODEN: COIDAZ; ISSN:1472-4472. (Thomson Scientific)A review. Daiichi Sankyo Co Ltd (formerly Daiichi Seiyaku Co Ltd) was developing the oral semisynthetic taxane deriv. tesetaxel for the potential treatment of cancer, including colorectal and gastric cancer. However, despite early signs of promise, in Nov. 2006 tesetaxel was removed from Daiichi's development pipeline for failure to show clear benefit over existing, currently marketed agents for cancer chemotherapy.(i) Baas, P.; Szczesna, A.; Albert, I.; Milanowski, J.; Juhasz, E.; Sztancsik, Z.; von Pawel, J.; Oyama, R.; Burgers, S. Phase I/II study of a 3 weekly oral taxane (DJ-927) in patients with recurrent, advanced non-small cell lung cancer. J. Thorac. Oncol. 2008, 3, 745– 750, DOI: 10.1097/JTO.0b013e31817c73ff[Crossref], [PubMed], [CAS], Google Scholar.88ihttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1cvisFemtA%253D%253D&md5=4ea3ea49273bb406aa94fe93696b31ddPhase I/II study of a 3 weekly oral taxane (DJ-927) in patients with recurrent, advanced non-small cell lung cancerBaas Paul; Szczesna A; Albert I; Milanowski J; Juhasz E; Sztancsik Z; von Pawel J; Oyama R; Burgers SJournal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer (2008), 3 (7), 745-50 ISSN:.INTRODUCTION: A phase I/II study was performed to assess the efficacy and toxicity of a new oral taxane in patients with recurrent, advanced Non-small Cell Lung Cancer. PATIENTS AND METHODS: Patients who were treated with one prior, taxane free chemotherapy regimen, were eligible for this study. A single oral dose of DJ-927 (27 mg/m) was given every 3 weeks. In case of good tolerance, one dose escalation to 35 mg/m was allowed. Response and toxicity were measured and plasma pharmacokinetic analysis was performed during the first course. RESULTS: From October 2004 to September 2005, 36 patients gave informed consent and 34 received medication. The mean age was 58 years (range, 33-75 years). The majority of patients were pretreated with a combination of cisplatin and gemcitabine. Median interval between end of first treatment and the registration of this study was 7 months (range, 0.8-22 months). Twelve patients died on study of which eight due to disease progression. In four patients with preexisting cardiac disease, toxicity led to cardiac worsening and subsequent death. Grade 3 and 4 toxicities according to the National Cancer Institute Common Toxicity Criteria were neutropenia in 18 patients (53%), anemia in six patients (18%), nausea and fatigue in two patients (6%), febrile neutropenia and neurotoxicity in one patient (3%). The overall response rate for all patients was 5.6% (Confidence Interval [CI] 0.7-18.7%). The percentage of patients with stabilization for >6 weeks was 47%. The median time to progression was 97 days (CI: 47-167 days) and the median survival time was 120 days (CI: 68-222 days) for the ITT group. Since only a minority of patients (3) tolerated the higher drug dose we omitted this dose level because of hematological toxicity. Pharmacokinetic analysis showed that the median area under the curve (t = 0-168 hours) was 1752 +/- 1355 ngr/ml/h and the half-life was 167 +/- 77 hours. CONCLUSION: When administered once every 3 weeks, this oral taxane formulation of DJ-927 was well-absorbed with a long terminal half-life of 167 +/- 77 hour. DJ-927 has antitumor activity against Non-small Cell Lung Cancer when given as second-line monotherapy (overall response rate in 5.6%; CI 0.7-18.7%). Ten patients experienced SD for more than 8 weeks. Different types of dose administration (metronomic dosing) or combination with other cytotoxic agents should be considered in future studies.(j) Al Idrus, A. Odonate abandons breast cancer chemo drug, closes its doors. https://www.fiercebiotech.com/biotech/odonate-abandons-breast-cancer-chemo-drug-closes-its-doors (accessed March 22, 2021).
- 89(a) Sakya, S. M.; Bertinato, P.; Pratt, B.; Suarez-Contreras, M.; Lundy, K. M.; Minich, M. L.; Cheng, H.; Ziegler, C. B.; Kamicker, B. J.; Hayashi, S. F.; Santoro, S. L.; George, D. W.; Bertsche, C. D. Azalide 3,6-ketals: antibacterial activity and structure-activity relationships of aryl and hetero aryl substituted analogues. Bioorg. Med. Chem. Lett. 2003, 13, 1373– 1375, DOI: 10.1016/S0960-894X(03)00100-8[Crossref], [PubMed], [CAS], Google Scholar.89ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXitlKjsbg%253D&md5=fafa8fa9a3c71eeeadafccadcfc39e90Azalide 3,6-Ketals: antibacterial activity and structure-Activity relationships of aryl and hetero aryl substituted analoguesSakya, Subas M.; Bertinato, Peter; Pratt, Bryan; Suarez-Contreras, Melani; Lundy, Kristin M.; Minich, Martha L.; Cheng, Hengmiao; Ziegler, Carl B.; Kamicker, Barbara J.; Hayashi, Shigeru F.; Santoro, Sheryl L.; George, David M.; Bertsche, Camilla D.Bioorganic & Medicinal Chemistry Letters (2003), 13 (7), 1373-1375CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science B.V.)Aryl and hetero aryl substituted 3,6-ketals of 15-membered azalide analogs were synthesized and were found to have potent in vitro antibacterial activity against veterinary pathogens, including Staphylococcus aureus and Pasteurella multocida.(b) Cheng, H.; Dirlam, J. P.; Ziegler, C. B.; Lundy, K. M.; Hayashi, S. F.; Kamicker, B. J.; Dutra, J. K.; Daniel, K. L.; Santoro, S. L.; George, D. M.; Bertsche, C. D.; Sakya, S. M.; Suarez-Contreras, M. Synthesis and SAR of azalide 3,6-ketal aromatic derivatives as potent Gram-positive and Gram-negative antibacterial agents. Bioorg. Med. Chem. Lett. 2002, 12, 2431– 2434, DOI: 10.1016/S0960-894X(02)00434-1[Crossref], [PubMed], [CAS], Google Scholar89bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XlvVGjuro%253D&md5=93dd0e36ee3a4283a9ee6e2e4c9f88d4Synthesis and SAR of azalide 3,6-ketal aromatic derivatives as potent gram-positive and gram-negative antibacterial agentsCheng, Hengmiao; Dirlam, John P.; Ziegler, Carl B.; Lundy, Kristin M.; Hayashi, Shigeru F.; Kamicker, Barbara J.; Dutra, Jason K.; Daniel, Kirsten L.; Santoro, Sheryl L.; George, David M.; Bertsche, Camilla D.; Sakya, Subas M.; Suarez-Contreras, MelaniBioorganic & Medicinal Chemistry Letters (2002), 12 (17), 2431-2434CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)3,6-Ketals of 15-membered azalide pseudoaglycones are a novel series of macrolide antibiotics. The arom. derivs. of the azalide 3,6-ketals demonstrated potent antibacterial activities against both Gram-pos. and Gram-neg. bacteria.
- 90Wu, Y.-J. Highlights of semi-synthetic developments from erythromycin A. Curr. Pharm. Des. 2000, 6, 181– 223, DOI: 10.2174/1381612003401316[Crossref], [PubMed], [CAS], Google Scholar90https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXhslWqsbc%253D&md5=e7d1d4a8af661440dece5604b0dd8a62Highlights of semi-synthetic developments from erythromycin AWu, Yong-JinCurrent Pharmaceutical Design (2000), 6 (2), 181-223CODEN: CPDEFP; ISSN:1381-6128. (Bentham Science Publishers)A review with 88 refs. Earlier semi-synthetic studies of erythromycin A culminated in the discovery of two successful second generation macrolide antibiotics, azithromycin and clarithromycin, for the treatment of community-acquired bacterial infections. More recent structural modifications of erythromycin A have resulted in the discovery of novel ketolide antibiotics and new motilide pro-kinetic agents. This review is an account of the semi-synthetic developments from erythromycin A by chem. transformations.
- 91(a) Luke, D. R.; Foulds, G. Disposition of oral azithromycin in humans. Clin. Pharmacol. Ther. 1997, 61, 641– 648, DOI: 10.1016/S0009-9236(97)90098-9[Crossref], [PubMed], [CAS], Google Scholar.91ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXkslalt7s%253D&md5=78bfa904ec3721bafc0978b2203f3e59Disposition of oral azithromycin in humansLuke, David R.; Foulds, GeorgeClinical Pharmacology and Therapeutics (St. Louis) (1997), 61 (6), 641-648CODEN: CLPTAT; ISSN:0009-9236. (Mosby-Year Book)The oral bioavailability of azithromycin is approx. 37% in healthy subjects; little is known about the disposition of the remaining 63% of the dose. This study attempted to describe the fate of azithromycin before absorption. Twelve subjects with ileostomies in place for >1 mo were studied in this open-label, randomized, three-center, two-period, two-treatment crossover study. Subjects randomly received a single 500 mg i.v. infusion (over 1 h) or two 250 mg oral capsules after a fast for >12 h. Blood and ileostomy samples were collected serially after each administration and analyzed for azithromycin and two metabolites (descladinose and 9a-N-desmethyl metabolites) by HPLC with electrochem. detection. Mean ± SD peak concn. values after oral and i.v. administration were 0.21 ± 0.08 and 3.40 ± 1.12 μg/mL. Mean values for area under the serum concn. vs. time curve were 1.27 ± 0.65 and 7.14 ± 1.34 μg · hr/mL, resp. The abs. bioavailability of 16.2% was approx. one-half the value obsd. previously in healthy subjects. Recovery in ileostomy fluid (percent of dose in 24 h) of azithromycin, descladinose, and 9a-N-desmethyl metabolites were 13%, 0.5%, and 1% (total, 15%) after i.v. dosing and 47%, 13%, and 2% (total, 62%) after oral dosing. Total and ileal clearances were 776 ± 126 and 158 ± 63 mL/min after i.v. dosing. Because more descladinose metabolite was detected after oral dosing, acid degrdn. of azithromycin before absorption contributed to some loss in oral bioavailability. Further, ileal clearance (biliary plus intestinal excretion clearance) in this population represented 21% of total clearance. Taken together, these data suggest that the cause of low oral bioavailability of azithromycin is the result of incomplete absorption rather than acid degrdn. or extensive first-pass metab.(b) Lode, H.; Borner, K.; Koeppe, P.; Schaberg, T. Azithromycin-review of key chemical, pharmacokinetic and microbiological features. J. Antimicrob. Chemother. 1996, 37, 1– 8, DOI: 10.1093/jac/37.suppl_C.1[Crossref], [PubMed], [CAS], Google Scholar.91bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XktlOit7o%253D&md5=d174b2fde0dc0f51c5140b445dcbe5f0Azithromycin - review of key chemical, Pharmacokinetic and microbiological featuresLode, H.; Borner, K.; Koeppe, P.; Schaberg, T.Journal of Antimicrobial Chemotherapy (1996), 37 (Suppl. C, Azithromycin: Further Clinical Experience), 1-8CODEN: JACHDX; ISSN:0305-7453. (Saunders)A review with 40 refs. One of the chem. features that distinguishes the 15-membered ring azalide azithromycin from the 14-membered ring macrolide compd. erythromycin is the former's increased stability at acid pH. Azithromycin also differs pharmacokinetically from erythromycin, and important feature being azithromycin's ability to achieve high tissue concns., with the agent being delivered to the sites of infection by direct uptake and by targeted delivery via phagocytes. High tissue concns. are maintained for prolonged periods because of azithromycin's long half-life, leading to once-daily dosing for 3 or 5 days. Notable microbiol. features of azithromycin are in-vitro activity against many pyogenic bacteria (e.g. Neisseria gonorrhoeae and Moraxella catarrhalis), as well as organisms against which β-lactam antibiotics are usually ineffective (e.g. Legionella and Chlamydia spp.), organisms that are resistant to benzylpenicillin and erythromycin (e.g. Haemophilus influenzae) and organisms for which satisfactory therapy is limited (e.g. Toxoplasma gondii and the Mycobacterium avium-intracellulare complex). These properties of azithromycin suggest that it might be a useful agent for the treatment of a wide range of bacterial infections.(c) Allin, D.; James, I.; Zachariah, J.; Carr, W.; Cullen, S.; Middleton, A.; Newson, P.; Lytle, T.; Coles, S. Comparison of once- and twice-daily clarithromycin in the treatment of adults with severe acute lower respiratory tract infections. Clin. Ther. 2001, 23, 1958– 1968, DOI: 10.1016/S0149-2918(01)80149-1[Crossref], [PubMed], [CAS], Google Scholar91chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XhtVyltLs%253D&md5=cf7296e8b1787c4d817c6b8de25992e1Comparison of once- and twice-daily clarithromycin in the treatment of adults with severe acute lower respiratory tract infectionsAllin, Dennis; James, Ian; Zachariah, Jollye; Carr, William; Cullen, Stephen; Middleton, Alan; Newson, Penny; Lytle, Thomas; Coles, StephenClinical Therapeutics (2001), 23 (12), 1958-1968CODEN: CLTHDG; ISSN:0149-2918. (Excerpta Medica, Inc.)Although the modified-release (MR) formulation of clarithromycin has demonstrated bioequivalence to the immediate-release (IR) formulation and thus can be prescribed for lower respiratory tract infections (LRTIs), a MEDLINE search from 1995 through 1998 and information on file with the manufacturer indicate that no data are available on the effectiveness of this new formulation in the treatment of severe LRTIs such as community-acquired pneumonia. This study was designed to compare clin. success rates (percentage of patients with clin. cure or improvement) with once- and twice-daily regimens of clarithromycin in the treatment of patients with severe, acute LRTIs requiring oral antibiotic therapy. In this multicenter, investigator-blinded, randomized, parallel-group study, adult patients with clin. evidence suggesting severe, acute LRTI were recruited from 22 general practices in the United Kingdom. Patients were randomly allocated to receive either clarithromycin 500 mg BID (IR tablets) or clarithromycin 1 g OD (two 500-mg MR tablets) for 7 to 14 days. The outcome measures were resoln. of or improvement in clin. signs and symptoms (including resoln. of cough), unscheduled visits for the same symptom, days to resumption of normal activities, and improvements in quality of life (assessed using the EQ-5D version of the EuroQoL questionnaire). Clin., microbiol., and serol. assessments were performed before, during, and after treatment. Efficacy and safety data were analyzed on an intent-to-treat basis. One hundred sixty men (n = 83) and women (n = 77) between the ages of 19 and 88 yr took part in the study, 78 receiving clarithromycin 500 mg BID and 82 receiving clarithromycin 1 g OD. At 4 wk after the start of treatment, the high clin. success rates were comparable between groups: 84.6% with clarithromycin 500 mg BID and 90.2% with clarithromycin 1 g OD. No significant differences in outcome measures were noted between the 2 regimens. Both treatments were well tolerated, with taste disturbance being the most commonly reported adverse event (10.6% vs. 6.1% with clarithromycin 500 mg BID and 1 g OD, resp.). The 2 clarithromycin regimens were equally efficacious and well tolerated in the treatment of severe, acute LRTIs. However, caution should be exercised in applying these results to the general population, because the study excluded certain categories of patients who would normally be treated. In addn., the small sample size may have obscured clin. significant differences between the 2 regimens.
- 92Botelho, A. F. M.; Pierezan, F.; Soto-Blanco, B.; Melo, M. M. A review of cardiac glycosides: structure, toxicokinetics, clinical signs, diagnosis and antineoplastic potential. Toxicon 2019, 158, 63– 68, DOI: 10.1016/j.toxicon.2018.11.429[Crossref], [PubMed], [CAS], Google Scholar92https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisVOjsrjL&md5=5e326c61b99905489fde9268ea6a18c4A review of cardiac glycosides: Structure, toxicokinetics, clinical signs, diagnosis and antineoplastic potentialBotelho, Ana Flavia M.; Pierezan, Felipe; Soto-Blanco, Benito; Melo, Marilia MartinsToxicon (2019), 158 (), 63-68CODEN: TOXIA6; ISSN:0041-0101. (Elsevier Ltd.)Cardiac glycosides (CGs) are secondary compds. found in plants and amphibians and are widely distributed in nature with potential cardiovascular action. Their mechanism is based on the blockage of the heart's sodium potassium ATPase, with a pos. inotropic effect. Some of the most well-known CGs are digoxin, ouabain, oleandrin, and bufalin. They have similar chem. structures: a lactone ring, steroid ring, and sugar moiety. Digoxin, ouabain, and oleandrin are classified as cardenolides, consisting of a lactone ring with five carbons, while bufalin is classified as bufodienolides, with a six-carbon ring. Small structural differences det. variations in the toxicokinetics and toxicodynamics of such substances. Most case reports of poisoning caused by CGs are assocd. with cardiovascular toxicity, causing a variety of arrhythmias and lesions in the heart tissue. Exptl. studies also describe important similarities among different CGs, esp. regarding species sensitivity. Recent studies furthermore focus on their antineoplastic potential, with controversial results. Data from research studies and case reports were reviewed to identify the main characteristics of the CGs, including toxicokinetics, toxicodynamics, clin. signs, electrocardiog., pathol. findings, antineoplastic potential and the main techniques used for diagnostic purposes.
- 93(a) Cohen, A.; Kroon, R.; Schoemaker, H.; Breimer, D.; Vliet-Verbeek, A.; Brandenburg, H. The bioavailability of digoxin from three oral formulations measured by a specific HPLC assay. Br. J. Clin. Pharmacol. 1993, 35, 136– 142, DOI: 10.1111/j.1365-2125.1993.tb05679.x[Crossref], [PubMed], [CAS], Google Scholar.93ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3sXitF2ltro%253D&md5=9179871c552baf9c603b9c715f90ac49The bioavailability of digoxin from three oral formulations measured by a specific HPLC assayCohen, A. F.; Kroon, R.; Schoemaker, H. C.; Breimer, D. D.; Van Vliet-Verbeek, A.; Brandenburg, H. C.British Journal of Clinical Pharmacology (1993), 35 (2), 136-42CODEN: BCPHBM; ISSN:0306-5251.The abs. bioavailability of three oral formulations of digoxin, 1.0 mg, was studied in 12 young healthy volunteers in a four way randomized cross-over study using an i.v. control. Digoxin tablets (250 μg), liq.-filled digoxin capsules (100 μg) and an exptl. enteric-coated capsule (100 μg) were evaluated. In vitro dissoln. at pH 1 demonstrated extensive hydrolytic breakdown of digoxin from the tablets and capsules but not from the enteric-coated capsules. Serum digoxin concns. were measured by fluorescence polarization immunoassay (FPI). The systemic availability of the capsules was 70.5%, and that of the tablets 71.5%. Drug was less available from the enteric-coated capsules (62.1%) measured with FPI. These results were reflected in the urinary drug recoveries measured by FPI. By contrast, there were no differences in urinary recovery of unchanged digoxin between any of the oral treatments, when this was measured by HPLC. The cross-reactivity of immunoassays for metabolites of digoxin may produce artifactual results and the optimal pharmaceutical formulation for digoxin remains to be detd.(b) Peters, U.; Falk, L. C.; Kalman, S. M. Digoxin metabolism in patients. Arch. Intern. Med. 1978, 138, 1074– 1076, DOI: 10.1001/archinte.1978.03630320018009[Crossref], [PubMed], [CAS], Google Scholar93bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaE1c3gvFOltg%253D%253D&md5=84140f281d5a4e2e2dc0fbdd12918645Digoxin metabolism in patientsPeters U; Falk L C; Kalman S MArchives of internal medicine (1978), 138 (7), 1074-6 ISSN:0003-9926.In 100 patients receiving digoxin to control heart disease, metabolic reduction of the lactone ring of digoxin was investigated. An average of 12.4% +/- 11% (range 2.2% to 52%) of the lipid-extractable cardenolides in a 24-hour urine sample contained the reduced lactone ring. Fifty-three excreted more than 10% while seven excreted more than 35% of these metabolic products. Reduction was not influenced by age, sex, dose, or blood level of digoxin. One patient who excreted 52% reduced products in the urine had 40% reduced digoxin-metabolites in the blood; the main metabolite was dihydrodigoxin. We found no influence of other drug therapy or concurrent disease on reduction of digoxin in this group.
- 94(a) Cowie, M. R.; Fisher, M. SGLT2 inhibitors: mechanisms of cardiovascular benefit beyond glycaemic control. Nat. Rev. Cardiol. 2020, 17, 761– 772, DOI: 10.1038/s41569-020-0406-8[Crossref], [PubMed], [CAS], Google Scholar.94ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtlynu7jL&md5=d3d6908db59d4e0a05e62071e53c3b45SGLT2 inhibitors: mechanisms of cardiovascular benefit beyond glycaemic controlCowie, Martin R.; Fisher, MilesNature Reviews Cardiology (2020), 17 (12), 761-772CODEN: NRCAE6; ISSN:1759-5002. (Nature Research)A Review. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are effective antidiabetic therapies in patients with type 2 diabetes mellitus and are assocd. with improved glycemic control as well as with redns. in body mass and blood pressure. In large cardiovascular outcome trials in patients with diabetes, SGLT2 inhibitors improve cardiovascular and renal outcomes, including hospitalization for heart failure, with this benefit extending to patients without diabetes who have heart failure with reduced ejection fraction. Early natriuresis with a redn. in plasma vol., a consequent rise in haematocrit, improved vascular function, a redn. in blood pressure and changes in tissue sodium handling are all likely to have a role. Addnl. mechanisms of SGLT2 inhibitors that might be beneficial include a redn. in adipose tissue-mediated inflammation and pro-inflammatory cytokine prodn., a shift towards ketone bodies as the metabolic substrate for the heart and kidneys, reduced oxidative stress, lowered serum uric acid level, reduced glomerular hyperfiltration and albuminuria, and suppression of advanced glycation end-product signalling. Further outcome trials and mechanistic studies, including in patients with heart failure with preserved ejection fraction or non-diabetic kidney disease, might identify other possible mechanisms of benefit of SGLT2-inhibitor therapy.(b) Moradi-Marjaneh, R.; Paseban, M.; Sahebkar, A. Natural products with SGLT2 inhibitory activity: possibilities of application for the treatment of diabetes. Phytother. Res. 2019, 33, 2518– 2530, DOI: 10.1002/ptr.6421[Crossref], [PubMed], [CAS], Google Scholar.94bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvFOis73N&md5=06b598d553e6844213e517a3d862588fNatural products with SGLT2 inhibitory activity: Possibilities of application for the treatment of diabetesMoradi-Marjaneh, Reyhaneh; Paseban, Maryam; Sahebkar, AmirhosseinPhytotherapy Research (2019), 33 (10), 2518-2530CODEN: PHYREH; ISSN:0951-418X. (John Wiley & Sons Ltd.)A review. Diabetes mellitus currently affects as many as 400 million people worldwide, creating a heavy economic burden and stretching health care resources. A dysfunction of glucose homeostasis underlies the disease. Despite advances in the treatment of diabetes, many patients still suffer from complications and side effects; hence, development of more effective treatments for diabetes is still desirable. SGLT2 is the principle cotransporter involved in glucose reabsorption in the kidney. SGLT2 inhibition reduces glucose reabsorption by the kidney and ameliorates plasma glucose concn. The interest in natural products that can be used for the inhibition of SGLT2 is growing. The flavonoid phlorizin, which can be isolated from the bark of apple trees, has been used as lead structure due to its inhibitory activity of SGLT1 and SGLT2. Some phlorizin-derived synthetic compds., including canagliflozin, dapagliflozin, empagliflozin, ipragliflozin, and ertugliflozin, are approved by the food and drug administration to treat type 2 diabetes mellitus (T2DM), whereas others are under clin. trials investigation. In addn., other natural product-derived compds. have been investigated for their ability to improve blood glucose control. The present review summarizes the natural products with SGLT2 inhibitory activity, and the synthetic compds. obtained from them, and discusses their application for the treatment of diabetes.(c) Mariadoss, A. V. A.; Vinyagam, R.; Rajamanickam, V.; Sankaran, V.; Venkatesan, S.; David, E. Pharmacological aspects and potential use of phloretin: a systemic review. Mini-Rev. Med. Chem. 2019, 19, 1060– 1067, DOI: 10.2174/1389557519666190311154425[Crossref], [PubMed], [CAS], Google Scholar94chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhslWrsb7K&md5=b07eeb707f93ddc5f31c17f021705755Pharmacological Aspects and Potential Use of Phloretin: A Systemic ReviewMariadoss, Arokia V. A.; Vinyagam, Ramachandran; Rajamanickam, Vinothkumar; Sankaran, Vijayalakshmi; Venkatesan, Sathish; David, ErnestMini-Reviews in Medicinal Chemistry (2019), 19 (13), 1060-1067CODEN: MMCIAE; ISSN:1389-5575. (Bentham Science Publishers Ltd.)A review. Over the past two decades, many researchers have concluded that a diet rich in polyphenolic compds. plays an important therapeutic role in reducing the risk of cancer, cardiovascular disease, inflammation, diabetes, and other degenerative diseases. Polyphenolic compds. have been reported to be involved in neutralization of reactive oxygen species and charged radicals, and have anticarcinogenic effects, hepatoprotective effects, low-glycemic response, and other benefits. The benefits of fruits and vegetables may be partly attributable to polyphenolic compds., which have antioxidant and free radical scavenging properties. Fruits such as apples contain a variety of phytochems., including (+)-catechin and (-)-epicatechin, phlorizin, phloretin quercetin, cyanidin-3-Ogalactoside, chlorogenic acid, and p-coumaric acid, all of which are strong antioxidants. Phloretin, a natural phenolic compd., is a dihydrochalcone, which is present in the apple. It exhibits a wide variety of activities such as antioxidative, anti-inflammatory, anti-microbial, anti-allergic, anticarcinogenic, anti-thrombotic, and hepatoprotective, besides being involved in the activation of apoptotic assocd. gene expression and signal transduction in mol. pathways. Despite a multitude of clin. studies, new efforts are needed in clin. research to det. the complete therapeutic potential of phloretin.
- 95Tsujihara, K.; Hongu, M.; Saito, K.; Kawanishi, H.; Kuriyama, K.; Matsumoto, M.; Oku, A.; Ueta, K.; Tsuda, M.; Saito, A. Na+-glucose cotransporter (SGLT) inhibitors as antidiabetic agents. 4. Synthesis and pharmacological properties of 4′-dehydroxyphlorizin derivatives substituted on the B ring. J. Med. Chem. 1999, 42, 5311– 5324, DOI: 10.1021/jm990175n[ACS Full Text], [CAS], Google Scholar95https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXnslSltbc%253D&md5=429449e4687602cac7866ef1bf279790Na+-Glucose Cotransporter (SGLT) Inhibitors as Antidiabetic Agents. 4. Synthesis and Pharmacological Properties of 4'-Dehydroxyphlorizin Derivatives Substituted on the B RingTsujihara, Kenji; Hongu, Mitsuya; Saito, Kunio; Kawanishi, Hiroyuki; Kuriyama, Kayoko; Matsumoto, Mamoru; Oku, Akira; Ueta, Kiichiro; Tsuda, Minoru; Saito, AkiraJournal of Medicinal Chemistry (1999), 42 (26), 5311-5324CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)In the authors' studies of Na+-glucose cotransporter (SGLT) inhibitors as antidiabetic agents, a series of novel 4'-dehydroxyphlorizin derivs. substituted on the B ring was prepd. and their effects on urinary glucose excretion were evaluated in rats. Introduction of only a small alkyl group at the 4'-position increased the activity, and 3-(benzo[b]furan-5-yl)-2',6'-dihydroxy-4'-methylpropiophenone 2'-O-β-D-glucopyranoside I (R = H) showed the most potent effect. To overcome hydrolysis by β-glucosidase in the digestive tract, the OH groups on the glucose moiety of I (R = H) were modified. Three prodrugs were more potent than the parent compd. by oral administration, and finally 3-(benzo[b]furan-5-yl)-2',6'-dihydroxy-4'-methylpropiophenone 2'-O-(6-O-methoxycarbonyl-β-D-glucopyranoside) I (R = CO2Me) was selected as a new promising candidate. This compd. was metabolized mainly by liver esterase to the active form, I (R = H) which was about 10 times more potent in inhibiting SGLT. In oral glucose tolerance test in db/db mice, I (R = CO2Me) dose-dependently suppressed the elevation of glucose levels. Single administration reduced hyperglycemia concurrently with increase of glucose excretion into urine in diabetic KK-Ay mice. Furthermore, I (R = CO2Me) suppressed the elevation of blood glucose levels but did not lower it below the normal level even in fasted conditions in KK-Ay mice. Addnl., long-term treatment dose-dependently reduced hyperglycemia and HbA1c in KK-Ay mice. These pharmacol. data strongly suggest that I (R = CO2Me) has a therapeutic potential in the treatment of NIDDM.
- 96Kees, K. L.; Fitzgerald, J. J., Jr.; Steiner, K. E.; Mattes, J. F.; Mihan, B.; Tosi, T.; Mondoro, D.; McCaleb, M. L. New potent antihyperglycemic agents in db/db mice: synthesis and structure-activity relationship studies of (4-substituted benzyl) (trifluoromethyl)pyrazoles and -pyrazolones. J. Med. Chem. 1996, 39, 3920– 3928, DOI: 10.1021/jm960444z[ACS Full Text], [CAS], Google Scholar96https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XlsVCisb8%253D&md5=76973cdadbffa8553a6c3bfd29116f79New Potent Antihyperglycemic Agents in db/db Mice: Synthesis and Structure-Activity Relationship Studies of (4-Substituted benzyl)(trifluoromethyl)pyrazoles and -pyrazolonesKees, Kenneth L.; Fitzgerald, John J., Jr.; Steiner, Kurt E.; Mattes, James F.; Mihan, Brenda; Tosi, Theresa; Mondoro, Diane; McCaleb, Michael L.Journal of Medicinal Chemistry (1996), 39 (20), 3920-3928CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The synthesis, structure-activity relation (SAR) studies, and antidiabetic characterization of 1,2-dihydro-4-[[4-(methylthio)phenyl]methyl]-5-(trifluoromethyl)-3H-pyrazol-3-one (as the hydroxy tautomer; WAY-123783, 4) are described. Substitution of 4-methylthio, methylsulfinyl, or Et to a benzyl group at C4, in combination with trifluoromethyl at C5 of pyrazol-3-one, generated potent antihyperglycemic agents in obese, diabetic db/db mice (16-30% redn. in plasma glucose at 2 mg/kg). The antihyperglycemic effect was assocd. with a robust glucosuria (>8 g/dL) obsd. in nondiabetic mice. Chem. trapping of four of the seven possible tautomeric forms of the heterocycle by mono- and dialkylation at the acidic hydrogens provided several addnl. potent analogs (39-43% redn. at 5 mg/kg) of the lead 4 as well as a dialkylated pair of regioisomers that showed sepn. of the assocd. glucosuric effect produced by all of the active analogs in normal mice. Further pharmacol. characterization of the lead WAY-123783 (ED50 = 9.85 mg/kg, po in db/db mice), in oral and s.c. glucose tolerance tests, indicated that unlike the renal and intestinal glucose absorption inhibitor phlorizin, pyrazolone 4 does not effectively block intestinal glucose absorption. SAR and addnl. pharmacol. data reported herein suggest that WAY-123783 represents a new class of potent antihyperglycemic agents which correct hyperglycemia by selective inhibition of renal tubular glucose resorption.
- 97(a) Washburn, W. N. Development of the renal glucose reabsorption inhibitors: a new mechanism for the pharmacotherapy of diabetes mellitus type 2. J. Med. Chem. 2009, 52, 1785– 1794, DOI: 10.1021/jm8013019[ACS Full Text.], [CAS], Google Scholar97ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXisVCjtbg%253D&md5=3ca641223da08b46057465fa2228f900Development of the Renal Glucose Reabsorption Inhibitors: A New Mechanism for the Pharmacotherapy of Diabetes Mellitus Type 2Washburn, William N.Journal of Medicinal Chemistry (2009), 52 (7), 1785-1794CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review.(b) Choi, C.-I. Sodium-glucose cotransporter 2 (SGLT2) inhibitors from natural products: discovery of next-generation antihyperglycemic agents. Molecules 2016, 21, 1136, DOI: 10.3390/molecules21091136[Crossref], [CAS], Google Scholar97bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslKis7rO&md5=68a60f0c2c669cf328bf9a123491f6c6Sodium-glucose cotransporter 2 (SGLT2) inhibitors from natural products: discovery of next-generation antihyperglycemic agentsChoi, Chang-IkMolecules (2016), 21 (9), 1136/1-1136/12CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)Diabetes mellitus is a chronic condition assocd. with the metabolic impairment of insulin actions, leading to the development of life-threatening complications. Although many kinds of oral antihyperglycemic agents with different therapeutic mechanisms have been marketed, their undesirable adverse effects, such as hypoglycemia, wt. gain, and hepato-renal toxicity, have increased demand for the discovery of novel, safer antidiabetic drugs. Since the important roles of the sodium-glucose cotransporter 2 (SGLT2) for glucose homeostasis in the kidney were recently elucidated, pharmacol. inhibition of SGLT2 has been considered a promising therapeutic target for the treatment of type 2 diabetes. Since the discovery of the first natural SGLT2 inhibitor, phlorizin, several synthetic glucoside analogs have been developed and introduced into the market. Furthermore, many efforts to find new active constituents with SGLT2 inhibition from natural products are still ongoing. This review introduces the history of research on the development of early-generation SGLT2 inhibitors, and recent progress on the discovery of novel candidates for SGLT2 inhibitor from several natural products that are widely used in traditional herbal medicine.
- 98(a) Shimizu, K.; Fujikura, H.; Fushimi, N.; Nishimura, T.; Tatani, K.; Katsuno, K.; Fujimori, Y.; Watanabe, S.; Hiratochi, M.; Nakabayashi, T.; Kamada, N.; Arakawa, K.; Hikawa, H.; Azumaya, I.; Isaji, M. Discovery of remogliflozin etabonate: A potent and highly selective SGLT2 inhibitor. Bioorg. Med. Chem. 2021, 34, 116033, DOI: 10.1016/j.bmc.2021.116033[Crossref], [PubMed], [CAS], Google Scholar.98ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXjvFOhtLs%253D&md5=849d17482f1d8b025c6c72b0d230808bDiscovery of remogliflozin etabonate: A potent and highly selective SGLT2 inhibitorShimizu, Kazuo; Fujikura, Hideki; Fushimi, Nobuhiko; Nishimura, Toshihiro; Tatani, Kazuya; Katsuno, Kenji; Fujimori, Yoshikazu; Watanabe, Shinjiro; Hiratochi, Masahiro; Nakabayashi, Takeshi; Kamada, Noboru; Arakawa, Koichi; Hikawa, Hidemasa; Azumaya, Isao; Isaji, MasayukiBioorganic & Medicinal Chemistry (2021), 34 (), 116033CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)We optimized the structure of an active metabolite (1) of WAY-123783, which was obtained from mouse urine after oral administration, to improve selectivity for SGLT2 and oral bioavailability. O-glucoside deriv. 24 (remogliflozin etabonate) was subsequently identified as a potent, highly selective, and orally available SGLT2 inhibitor.(b) Sigafoos, J. F.; Bowers, G. D.; Castellino, S.; Culp, A. G.; Wagner, D. S.; Reese, M. J.; Humphreys, J. E.; Hussey, E. K.; O’Connor Semmes, R. L.; Kapur, A.; Tao, W.; Dobbins, R. L.; Polli, J. Assessment of the drug interaction risk for remogliflozin etabonate, a sodium-dependent glucose cotransporter-2 inhibitor: evidence from in vitro, human mass balance, and ketoconazole interaction studies. Drug Metab. Dispos. 2012, 40, 2090– 2101, DOI: 10.1124/dmd.112.047258[Crossref], [PubMed], [CAS], Google Scholar.98bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsFKkt73L&md5=e416fe362dec69d516bc6dee55988d92Assessment of the drug interaction risk for remogliflozin etabonate, a sodium-dependent glucose cotransporter-2 inhibitor: evidence from in vitro, human mass balance, and ketoconazole interaction studiesSigafoos, James F.; Bowers, Gary D.; Castellino, Stephen; Culp, Amanda G.; Wagner, David S.; Reese, Melinda J.; Humphreys, Joan E.; Hussey, Elizabeth K.; Semmes, Robin L. O'Connor; Kapur, Anita; Tao, Wenli; Dobbins, Robert L.; Polli, Joseph W.Drug Metabolism & Disposition (2012), 40 (11), 2090-2101CODEN: DMDSAI; ISSN:1521-009X. (American Society for Pharmacology and Experimental Therapeutics)Remogliflozin etabonate is the ester prodrug of remogliflozin, a selective sodium-dependent glucose cotransporter-2 inhibitor. This work investigated the absorption, metab., and excretion of [14C]remogliflozin etabonate in humans, as well as the influence of P-glycoprotein (Pgp) and cytochrome P 450 (P 450) enzymes on the disposition of remogliflozin etabonate and its metabolites to understand the risks for drug interactions. After a single oral 402 ± 1.0 mg (106 ± 0.3 μCi) dose, [14C]remogliflozin etabonate is rapidly absorbed and extensively metabolized. The area under the concn.-time curve from 0 to infinity [AUC(0-∞)] of plasma radioactivity was approx. 14-fold higher than the sum of the AUC(0-∞) of remogliflozin etabonate, remogliflozin, and 5-methyl-4-({4-[(1-methylethyl)oxy]phenyl}methyl)-1H-pyrazol-3-yl-β-D-glucopyranoside (GSK279782), a pharmacol. active N-dealkylated metabolite. Elimination half-lives of total radioactivity, remogliflozin etabonate, and remogliflozin were 6.57, 0.39, and 1.57 h, resp. Products of remogliflozin etabonate metab. are eliminated primarily via renal excretion, with 92.8% of the dose recovered in the urine. Three glucuronide metabolites made up the majority of the radioactivity in plasma and represent 67.1% of the dose in urine, with 5-methyl-1-(1-methylethyl)-4-({4-[(1-methylethyl)oxy]phenyl}methyl)-1H-pyrazol-3-yl-β-D-glucopyranosiduronic acid (GSK1997711) representing 47.8% of the dose. In vitro studies demonstrated that remogliflozin etabonate and remogliflozin are Pgp substrates, and that CYP3A4 can form GSK279782 directly from remogliflozin. A ketoconazole clin. drug interaction study, along with the human mass balance findings, confirmed that CYP3A4 contributes less than 50% to remogliflozin metab., demonstrating that other enzyme pathways (e.g., P450s, UDP-glucuronosyltransferases, and glucosidases) make significant contributions to the drug's clearance. Overall, these studies support a low clin. drug interaction risk for remogliflozin etabonate due to the availability of multiple biotransformation pathways.(c) Kapur, A.; O’Connor-Semmes, R.; Hussey, E. K.; Dobbins, R. L.; Tao, W.; Hompesch, M.; Smith, G. A.; Polli, J. W.; James, C. D. Jr.; Mikoshiba, I.; Nunez, D. J. First human dose-escalation study with remogliflozin etabonate, a selective inhibitor of the sodium-glucose transporter 2 (SGLT2), in healthy subjects and in subjects with type 2 diabetes mellitus. BMC Pharmacol. Toxicol. 2013, 14, 26, DOI: 10.1186/2050-6511-14-26[Crossref], [PubMed], [CAS], Google Scholar98chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtFCntL3N&md5=b604de376b31602bf111b4b82ad9a7eeFirst human dose-escalation study with remogliflozin etabonate, a selective inhibitor of the sodium-glucose transporter 2 (SGLT2), in healthy subjects and in subjects with type 2 diabetes mellitusKapur, Anita; O'Connor-Semmes, Robin; Hussey, Elizabeth K.; Dobbins, Robert L.; Tao, Wenli; Hompesch, Marcus; Smith, Glenn A.; Polli, Joseph W.; James, Charles D., Jr.; Mikoshiba, Imao; Nunez, Derek J.BMC Pharmacology and Toxicology (2013), 14 (), 26CODEN: BPTMAB; ISSN:2050-6511. (BioMed Central Ltd.)Background: Remogliflozin etabonate (RE) is the prodrug of remogliflozin, a selective inhibitor of the renal sodium dependent glucose transporter 2 (SGLT2), which could increase urine glucose excretion (UGE) and lower plasma glucose in humans. Methods: This double blind, randomized, placebo controlled, single dose, dose escalation, crossover study is the first human trial designed to evaluate safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of RE. All subjects received single oral doses of either RE or placebo sepd. by approx. 2 wk intervals. In Part A, 10 healthy subjects participated in 5 dosing periods where they received RE (20 mg, 50 mg, 150 mg, 500 mg or 1000 mg) or placebo (4:1 active to placebo ratio per treatment period). In Part B, 6 subjects with type 2 diabetes mellitus (T2DM) participated in 3 dose periods where they received RE (50 mg and 500 mg) or placebo (2:1 active to placebo per treatment period). The study protocol was registered with the NIH clin. trials data base with identifier NCT01571661. Results: RE was generally well tolerated; there were no serious adverse events. In both populations, RE was rapidly absorbed and converted to remogliflozin (time to max. plasma concn. [Cmax;Tmax] approx. 1 h). Generally, exposure to remogliflozin was proportional to the administered dose. RE was rapidly eliminated (mean T1/2 of ∼25 min; mean plasma T1/2 for remogliflozin was 120 min) and was independent of dose. All subjects showed dose dependent increases in 24-h UGE, which plateaued at approx. 200 to 250 mmol glucose with RE doses ≥150 mg. In T2DM subjects, increased plasma glucose following OGTT was attenuated by RE in a drug dependent fashion, but there were no clear trends in plasma insulin. There were no apparent effects of treatment on plasma or urine electrolytes. Conclusions: The results support progression of RE as a potential treatment for T2DM.
- 99(a) Mohan, V.; Mithal, A.; Joshi, S. R.; Aravind, S. R.; Chowdhury, S. Remogliflozin etabonate in the treatment of type 2 diabetes: design, development, and place in therapy. Drug Des., Dev. Ther. 2020, 14, 2487– 2501, DOI: 10.2147/DDDT.S221093[Crossref], [PubMed], [CAS], Google Scholar.99ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXisFalsbrL&md5=95d0cff5e02f9a4c5743b4f9b0081e55Remogliflozin etabonate in the treatment of type 2 diabetes: design, development, and place in therapyMohan, Viswanathan; Mithal, Ambrish; Joshi, Shashank R.; Aravind, S. R.; Chowdhury, SubhankarDrug Design, Development and Therapy (2020), 14 (), 2487-2501CODEN: DDDTAQ; ISSN:1177-8881. (Dove Medical Press Ltd.)Type 2 diabetes mellitus (T2DM) is an emerging epidemic in Asian countries, esp. in India. With the advent of the SGLT2 inhibitor class of drugs demonstrating benefits beyond glycemic control, viz. wt. loss, blood pressure redn., and cardiovascular and renal protection, the management of T2DM has taken a quantum leap. Remogliflozin etabonate (RE) is the latest addn. to the SGLT2 inhibitor class of drugs that have been recently approved in India for the management of T2DM. RE is a potent and selective inhibitor of SGLT2 with the unique distinction of being administered as a prodrug, existence of active metabolites, and short half-life necessitating twice-daily dosing. The Phase III study of RE demonstrated it to be an efficacious and safe agent and non-inferior to the currently available SGLT2 inhibitors. This paper reviews not only the pharmacokinetics, pharmacodynamics, clin. efficacy, and safety profile of RE but also its mol. and clin. development program. This review has taken into consideration all available published as well as unpublished literature on RE and discusses the individual studies performed during its development for characterization of pharmacol. profile.(b) Markham, A. Remogliflozin etabonate: first global approval. Drugs 2019, 79, 1157– 1161, DOI: 10.1007/s40265-019-01150-9[Crossref], [PubMed], [CAS], Google Scholar99bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtFyisrjP&md5=d599b50ff2c1d3131e7d3dbbc2ce663fRemogliflozin Etabonate: First Global ApprovalMarkham, AnthonyDrugs (2019), 79 (10), 1157-1161CODEN: DRUGAY; ISSN:0012-6667. (Springer International Publishing AG)A review. Remogliflozin, a selective sodium-glucose co-transporter subtype 2 (SGLT2) inhibitor, which is to be administered as remogliflozin etabonate (Remo, Remozen), the prodrug for remogliflozin, recently received its first approval as a treatment for type 2 diabetes mellitus (T2DM) in India. This article summarizes the milestones in the development of remogliflozin etabonate leading to this first approval for T2DM.
- 100Ting, H. J.; Murad, J. P.; Espinosa, E. V. P.; Khasawneh, F. T. Thromboxane A2 receptor: biology and function of a peculiar receptor that remains resistant for therapeutic targeting. J. Cardiovasc. Pharmacol. Ther. 2012, 17, 248– 259, DOI: 10.1177/1074248411424145[Crossref], [PubMed], [CAS], Google Scholar100https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtlCqtLjO&md5=461dd114846130ee068e7be9005c235fThromboxane A2 receptor: biology and function of a peculiar receptor that remains resistant for therapeutic targetingTing, Harold J.; Murad, John P.; Espinosa, Enma V. P.; Khasawneh, Fadi T.Journal of Cardiovascular Pharmacology and Therapeutics (2012), 17 (3), 248-259CODEN: JCPTFE; ISSN:1074-2484. (Sage Publications)A review. While blood platelets express several G-protein-coupled receptors (GPCRs) that play pivotal roles in their activation, several diseases, for example thrombotic disorders, may develop if these receptors are inappropriately activated. Thus, these receptors have been the subject of investigations to design therapeutic interventions for managing multiple thrombosis-based disease states. One such GPCR, the thromboxane A2 receptor (TPR), remains resistant to such interventions. The present review provides a crit. examn. of the binding, structural biol., and signaling of TPRs. The review also provides a rationale for using principles of "drug rediscovery" as an alternative/viable approach for the therapeutic targeting of TPRs. To this end, it is noteworthy that many US Food and Drug Administration (FDA)-approved drugs have been found to selectively (and nonselectively) block TPR-mediated functional responses, for example platelet aggregation, as described in this review. Therefore, while none of the antagonists, thus far developed for targeting TPRs, have made it into clin. use, this peculiar receptor can be antagonized by a large no. of drugs used for indications unrelated to thrombosis.
- 101(a) Fried, J.; John, V.; Szwedo, M. J., Jr.; Chen, C.; O’Yang, C.; Morinelli, T. A.; Okwu, A. K.; Halushka, P. V. Synthesis of 10,10-difluorothromboxane A2, a potent and chemically stable thromboxane agonist. J. Am. Chem. Soc. 1989, 111, 4510– 4511, DOI: 10.1021/ja00194a062[ACS Full Text.], [CAS], Google Scholar101ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1MXkslOlurg%253D&md5=d7e0d48fabf0168ed2452a0f97a21b09Synthesis of 10,10-difluorothromboxane A2, a potent and chemically stable thromboxane agonistFried, Josef; John, Varghese; Szwedo, Mitchell J., Jr.; Chen, Chien Kuang; O'Yang, Counde; Morinelli, Thomas A.; Okwu, Anselm K.; Halushka, Perry V.Journal of the American Chemical Society (1989), 111 (12), 4510-11CODEN: JACSAT; ISSN:0002-7863.The total synthesis of 10,10-difluorothromboxane A2 (I), the first stable analog of thromboxane A2 (TXA2) possessing the dioxa[3.1.1]bicycloheptane nucleus, and of three stereoisomers is described. The starting material is the racemic dibenzyl ether II (R = CH2Ph) which contains the 7,7-difluoro-2,6-dioxa[3.1.1]bicycloheptane system previously shown to undergo hydrolytic cleavage of the oxetane ring at 10-8 times the rate of TXA2 (R. Noyori et al. 1984). The key reaction in this synthesis is the regio- and enantiospecific enzymic hydrolysis of II (R = Ac) to the (+)-monoacetate, which was converted to the target compds. without hydrolytic cleavage of the oxetane ring during any one of the synthetic steps. I stimulated platelet aggregation and contraction of saphenous veins at potencies similar to those of TXA2. The three stereoisomeric compds. were receptor antagonists in platelets but were agonists in saphenous veins, indicating two types of thromboxane receptors.(b) Morinelli, T. A.; Okwu, A. K.; Mais, D. E.; Halushka, P. V.; John, V.; Chen, C. K.; Fried, J. Difluorothromboxane A2 and stereoisomers: stable derivatives of thromboxane A2 with differential effects on platelets and blood vessels. Proc. Natl. Acad. Sci. U. S. A. 1989, 86, 5600– 5604, DOI: 10.1073/pnas.86.14.5600[Crossref], [PubMed], [CAS], Google Scholar.101bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1MXlt1Oiu78%253D&md5=b4661df86a2fa237f549265a2a1e5bd5Difluorothromboxane A2 and stereoisomers: stable derivatives of thromboxane A2 with differential effects on platelets and blood vesselsMorinelli, Thomas A.; Okwu, Anselm K.; Mais, Dale E.; Halushka, Perry V.; John, Varghese; Chen, Chien Kuang; Fried, JosefProceedings of the National Academy of Sciences of the United States of America (1989), 86 (14), 5600-4CODEN: PNASA6; ISSN:0027-8424.The selective effects on human platelets and canine saphenous veins of 4 stable difluorinated TXA2 analogs and TXA2 in which the characteristic 2,6-dioxa[3.1.1]bicycloheptane structure of TXA2 has been retained was studied. The 4 compds. differ in the stereochem. of the 5,6 double bond and(or) the 15-hydroxyl group. Only 10,10-difluoro-TXA2 (I) with the natural stereochem. of TXA2 was an agonist in both platelets and canine saphenous veins (EC50 = 36 nM and 3.7 nM, resp.)9. (15R)-10,10-Difluoro-TXA2 (II), (5E)-10,10-difluoro-TXA2 (III), and (5E,15R)-10,10-difluoro-TXA2 (IV) were antagonists of platelet aggregation stimulated by compd. I (Kd = 98, 140, and 1450 nM, resp.). However, II, III, and IV stimulated contraction of canine saphenous veins (EC50 = 36, 31, and 321 nM, resp.). All 4 compds. displaced the TXA2/PGH2 antagonist 9,11-dimethylmethano-11,12-methano-16-(3-125I-4-hydroxyphenyl)-13,14-dihydro-13-aza-15αβ-ω-tetranor-TXA2 from its platelet receptor (Kd values = 100 nM, I; 280 nM, II; 230 nM, III; and 1410 nM, IV). These results support the existence of 2 subtypes of TXA2/PGH2 receptors and emphasize the importance of the stereochem. requirements of these TXA2 analogs for interaction with these receptors. These stable fluorinated TXA2 analogs should prove useful tools for the further characterization of these and other TXA2/PGH2 receptors.(c) Jing, C.; Mallah, S.; Kriemen, E.; Bennett, S. H.; Fasano, V.; Lennox, A. J.; Hers, I.; Aggarwal, V. K. Synthesis, stability, and biological studies of fluorinated analogues of thromboxane A2. ACS Cent. Sci. 2020, 6, 995– 1000, DOI: 10.1021/acscentsci.0c00310[ACS Full Text.], [CAS], Google Scholar101chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtFWjsLjO&md5=bab9b0261524b2585dd6a724ec9208aeSynthesis, Stability, and Biological Studies of Fluorinated Analogues of Thromboxane A2Jing, Changcheng; Mallah, Shahida; Kriemen, Ella; Bennett, Steven H.; Fasano, Valerio; Lennox, Alastair J. J.; Hers, Ingeborg; Aggarwal, Varinder K.ACS Central Science (2020), 6 (6), 995-1000CODEN: ACSCII; ISSN:2374-7951. (American Chemical Society)Platelet activation results in the generation of thromboxane A2 (TxA2), which promotes thrombus formation by further amplifying platelet function, as well as causing vasoconstriction. Due to its role in thrombus formation and cardiovascular disease, its prodn. is the target of antiplatelet drugs such as aspirin. However, the study of TxA2-stimulated cellular function has been limited by its instability (t1/2 = 32 s, pH = 7.4). Although more stable analogs such as U46619 and difluorinated 10,10-F2-TxA2 have been prepd., we targeted a closer mimic to TxA2 itself, monofluorinated 10-F-TxA2, since the no. of fluorine atoms can affect function. Key steps in the synthesis of F-TxA2 included α-fluorination of a lactone bearing a β-alkoxy group, and a novel synthesis of the strained acetal. F-TxA2 was found to be 105 more stable than TxA2, and surprisingly was only slightly less stable than F2-TxA2. Preliminary biol. studies showed that F-TxA2 has similar potency as TxA2 toward inducing platelet aggregation but was superior to F2-TxA2 in activating integrin αIIbβ3. The synthesis is described of 10-F-thromboxane A2 I, a stable mimic of TxA2 (105 x more stable) with similar potency as TxA2 toward inducing platelet aggregation.(d) Schaaf, T. R.; Bussolotti, D. L.; Parry, M. J.; Corey, E. J. Synthesis of 11a,9a-epoxymethanothromboxane A2: a stable, optically active TxA2 agonist. J. Am. Chem. Soc. 1981, 103, 6502– 6505, DOI: 10.1021/ja00411a044[ACS Full Text], [CAS], Google Scholar101dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL3MXlvFOhsLg%253D&md5=a3a1c37ecc21aa5519009c5f58d3c192Synthesis of 11α,9α-epoxymethanothromboxane A2: a stable, optically active TxA2 agonistSchaaf, Thomas K.; Bussolotti, Donald L.; Parry, M. John; Corey, E. J.Journal of the American Chemical Society (1981), 103 (21), 6502-5CODEN: JACSAT; ISSN:0002-7863.11α,9α-Epoxymethanothromboxane A2 (I) [79440-53-2], a chem. stable, chiral homolog of thromboxane A2 (TxA2), and II [79440-72-5] were synthesized and tested pharmacol. The synthesis of I involved the formal stereoselective insertion of a methylene unit into the lactone of chiral III [62158-33-2], acid catalyzed formation of the bridged THF moiety and elaboration of the side chains. Initial pharmacol. evaluation indicates that I inhibits TxA2 agonist activity in rabbit platelet rich plasma and on the isolated rabbit aorta, is devoid of antagonist effects in these systems, and is without appreciable thromboxane synthetase inhibiting activity.
- 102(a) Longridge, J. L.; Nicholson, S. The alkaline stability of (5Z)-7-([2RS,4RS,5SR]-4-o-hydroxyphenyl-2-trifluoromethyl-1,3-dioxan-5-yl)hept-5-enoic acid, ICI 185282. A remarkable intramolecular hydride transfer from a trifluoromethyl substituted carbon atom. J. Chem. Soc., Perkin Trans. 2 1990, 965– 970, DOI: 10.1039/p29900000965[Crossref], [CAS], Google Scholar.102ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3cXlslWhsbY%253D&md5=689f8f75ca9d4049da56914d6c8a829dThe alkaline stability of (5Z)-7-([2RS,4RS,5SR]-4-(o-hydroxyphenyl)-2-(trifluoromethyl)-1,3-dioxan-5-yl)hept-5-enoic acid, ICI 185282. A remarkable intramolecular hydride transfer from a trifluoromethyl substituted carbon atomLongridge, Jethro L.; Nicholson, StuartJournal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999) (1990), (6), 965-70CODEN: JCPKBH; ISSN:0300-9580.The kinetics of hydrolysis of (5Z)-7-([2RS,4RS,5SR]-2-trifluoromethyl-1,3-dioxan-5-yl)hept-5-enoic acid, ICI 185282, have been studied. At low pH the compd. undergoes conventional acid-catalyzed hydrolysis of the dioxane ring. However, under alk. conditions, a second reaction is obsd. Studies by NMR show that this process involves a quite unexpected intramol. hydride transfer from a carbon atom carrying a strongly electron-withdrawing trifluoromethyl substituent. Addnl. studies on closely related compds. are reported and a mechanism involving a ring-opened quinone methide intermediate is proposed.(b) Brewster, A. G.; Brown, G. R.; Foubister, A. J.; Jessup, R.; Smithers, M. J. The synthesis of a novel thromboxane receptor antagonist 4(Z)-6-(2-o-chlorophenyl-4-o-hydroxyphenyl-1,3-dioxan-cis-5-yl) hexenoic acid ICI 192605. Prostaglandins 1988, 36, 173– 178, DOI: 10.1016/0090-6980(88)90304-8[Crossref], [PubMed], [CAS], Google Scholar102bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1MXltVY%253D&md5=04aef2317af13fda6b3549eeed195307The synthesis of a novel thromboxane receptor antagonist 4(Z)-6-(2-0-chlorophenyl-4-0-hydroxyphenyl-1,3-dioxan-cis-5-yl)hexenoic acid, ICI 192605Brewster, A. G.; Brown, G. R.; Foubister, A. J.; Jessup, R.; Smithers, M. J.Prostaglandins (1988), 36 (2), 173-8CODEN: PRGLBA; ISSN:0090-6980.The title compd. (I) was prepd. and its pharmacol. as a thromboxane receptor antagonist were studied in humans and lab. animals in vivo and in vitro.
- 103(a) O’Neill, P. M.; Posner, G. H. A medicinal chemistry perspective on artemisinin and related endoperoxides. J. Med. Chem. 2004, 47, 2945– 2964, DOI: 10.1021/jm030571c[ACS Full Text.], [CAS], Google Scholar103ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXjvVSgsrc%253D&md5=d39dbc04bfb86ab753bbe96d52411070A Medicinal Chemistry Perspective on Artemisinin and Related EndoperoxidesO'Neill, Paul M.; Posner, Gary H.Journal of Medicinal Chemistry (2004), 47 (12), 2945-2964CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review on aspects of the chem., mechanism of action, metab., and toxicity of the endoperoxide class of antimalarial drugs with a focus on lead compds. (semisynthetic and synthetic) that have emerged as potential next-generation analogs. The authors also briefly cover artemisinin combination therapy (ACT) of malaria and discuss the potential of drug hybrids and prodrugs as new approaches to delivering combination chemotherapy through a sing.(b) Krishna, S.; Bustamante, L.; Haynes, T. K.; Staines, H. M. Artemisinins: their growing importance in medicine. Trends Pharmacol. Sci. 2008, 29, 520– 527, DOI: 10.1016/j.tips.2008.07.004[Crossref], [PubMed], [CAS], Google Scholar103bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtFOmurjL&md5=a074709688abde63c63e67f14c6cdab5Artemisinins: their growing importance in medicineKrishna, Sanjeev; Bustamante, Leyla; Haynes, Richard K.; Staines, Henry M.Trends in Pharmacological Sciences (2008), 29 (10), 520-527CODEN: TPHSDY; ISSN:0165-6147. (Elsevier B.V.)A review. Artemisinins are derived from exts. of sweet wormwood (Artemisia annua) and are well established for the treatment of malaria, including highly drug-resistant strains. Their efficacy also extends to phylogenetically unrelated parasitic infections such as schistosomiasis. More recently, they have also shown potent and broad anticancer properties in cell lines and animal models. In this review, we discuss recent advances in defining the role of artemisinins in medicine, with particular focus on their controversial mechanisms of action. This safe and cheap drug class that saves lives at risk from malaria can also have important potential in oncol.
- 104(a) Ilett, K. F.; Ethell, B. T.; Maggs, J. L.; Davis, D. M. E.; Batty, K. T.; Burchell, B.; Binh, T. W.; Thu, L. T.; Hung, N. C.; Pirmohamed, M.; Park, B. K.; Edwards, G. Glucuronidation of dihydroartemisinin in vivo and by human liver microsomes and expressed UDP-glucuronosyltransferases. Drug Metab. Dispos. 2002, 30, 1005– 1012, DOI: 10.1124/dmd.30.9.1005[Crossref], [PubMed], [CAS], Google Scholar.104ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XmsVShurY%253D&md5=692a3619c62277bcdad8b113338d943bGlucuronidation of dihydroartemisinin in vivo and by human liver microsomes and expressed UDP-glucuronosyltransferasesIlett, Kenneth F.; Ethell, Brian T.; Maggs, James L.; Davis, Timothy M. E.; Batty, Kevin T.; Burchell, Brian; Binh, Tran Quang; Thu, Le Thi Anh; Hung, Nguyen Canh; Pirmohamed, Munir; Park, B. Kevin; Edwards, GeoffreyDrug Metabolism and Disposition (2002), 30 (9), 1005-1012CODEN: DMDSAI; ISSN:0090-9556. (American Society for Pharmacology and Experimental Therapeutics)This work studied the metabolic pathways of dihydroartemisinin (DHA), the active metabolite of the artemisinin deriv. artesunate (ARTS). Urine was collected from Vietnamese adults with falciparum malaria who had received 120 mg ARTS i.v., and metabolites were analyzed by HPLC-mass spectrometry (HPLC-MS). Human liver microsomes were also incubated with [12-3H]DHA and cofactors for either glucuronidation or cytochrome P 450-catalyzed oxidn. Human liver cytosol was incubated with a cofactor for sulfation. Metabolites were detected by HPLC-MS and/or HPLC with radiochem. detection. Metab. of DHA by recombinant human UDP-glucuronosyltransferases (UGTs) was studied. HPLC-MS anal. of urine identified α-DHA-β-glucuronide (α-DHA-G) and a product characterized as the THF isomer of α-DHA-G. DHA was present only in very small amts. The ratio of the THF isomer to α-DHA-G was highly variable (median 0.75; range 0.09-64). Nevertheless, α-DHA-G was generally the major urinary product of DHA glucuronidation in patients. The THF isomer appeared to be at least partly a product of nonenzymic reactions occurring in urine and was readily formed from α-DHA-G by iron-mediated isomerization. In human liver microsomal incubations, DHA-G (diastereomer unspecified) was the only metabolite found (Vmax 177 pmol/min/mg, Km 90 μM). α-DHA-G was formed in incubations of DHA with expressed UGT1A9 (Km 32 μM, Vmax 8.9 pmol/mg/min) or UGT2B7 (Km 438 μM, Vmax 10.9 pmol/mg/min) but not with UGT1A1 or UGT1A6. There was no significant metab. of DHA by cytochrome P 450 oxidn. or by cytosolic sulfotransferases. It is concluded that α-DHA-G is an important metabolite of DHA in humans and that its formation is catalyzed by UGT1A9 and UGT2B7.(b) O’Neill, P. M.; Scheinmann, F.; Stachulski, A. V.; Maggs, J. L.; Park, B. K. Efficient preparations of the α-glucuronides of dihydroartemisinin and structural confirmation of the human glucuronide metabolite. J. Med. Chem. 2001, 44, 1467– 1470, DOI: 10.1021/jm001061a[ACS Full Text], [CAS], Google Scholar104bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXislKju7s%253D&md5=8e83e257700e07fef45568475e78ae4fEfficient Preparations of the β-Glucuronides of Dihydroartemisinin and Structural Confirmation of the Human Glucuronide MetaboliteO'Neill, Paul M.; Scheinmann, Feodor; Stachulski, Andrew V.; Maggs, James L.; Park, B. KevinJournal of Medicinal Chemistry (2001), 44 (9), 1467-1470CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)New and greatly improved prepns. of the 12α,1'β- and 12β,1'β-glucuronides of dihydroartemisinin (DHA) are reported using anomeric hydroxy and imidate glucuronate intermediates. Comparison of the synthetic and natural materials shows that the human metabolite of DHA is the 12α-epimer.
- 105(a) Nga, T. T. T.; Menage, C.; Begue, J.-P.; Bonnet-Delpon, D.; Gantier, J.-C.; Pradines, B.; Doury, J.-C.; Thac, T. D. Synthesis and antimalarial activities of fluoroalkyl derivatives of dihydroartemisinin. J. Med. Chem. 1998, 41, 4101– 4108, DOI: 10.1021/jm9810147[ACS Full Text.], [CAS], Google Scholar105ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXlvFGitbg%253D&md5=687617ce7330b1e931a7b8f006886bfaSynthesis and Antimalarial Activities of Fluoroalkyl Derivatives of DihydroartemisininNga, Truong Thi Thanh; Menage, Celine; Begue, Jean-Pierre; Bonnet-Delpon, Daniele; Gantier, Jean-Charles; Pradines, Bruno; Doury, Jean-Claude; Thac, Truong DinhJournal of Medicinal Chemistry (1998), 41 (21), 4101-4108CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Fluoroalkyl ethers of dihydroartemisinin were prepd. via the reaction of fluoroalkyl alcs. with dihydroartemisinin using different methods (BF3,Et2O or TMSCl catalysis or Mitsunobu reaction). Ethers I (R = CF3, CF2CF3, CF2CF2CF3, CF2CHFCF3; R1 = R2 = H) derived from primary fluoroalkyl alcs. were obtained in moderate to good yields by these methods. Ethers I, e.g. (R =CF3, R1 = Ph, R2 = H; R=R1 = CF3, R2 = H; R=R1=R2 = C6H5) were prepd. from fluoroalkyl secondary and tertiary alcs. and phenol using the Mitsunobu reaction. In vitro antimalarial activities of ethers toward Plasmodium falciparum W-2 asiatic strain are moderate while in vivo activities against Plasmodium berghei (NT 173) were excellent.(b) Magueur, G.; Crousse, B.; Charneau, S.; Grellier, P.; Begue, J.-P.; Bonnet-Delpon, D. Fluoroartemisinin: trifluoromethyl analogues of artemether and artesunate. J. Med. Chem. 2004, 47, 2694– 2699, DOI: 10.1021/jm0310333[ACS Full Text.], [CAS], Google Scholar105bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXisl2it7o%253D&md5=8f35ed345b0011c56c6154ac7405800bFluoroartemisinin: Trifluoromethyl Analogues of Artemether and ArtesunateMagueur, Guillaume; Crousse, Benoit; Charneau, Sebastien; Grellier, Philippe; Begue, Jean-Pierre; Bonnet-Delpon, DanieleJournal of Medicinal Chemistry (2004), 47 (10), 2694-2699CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The synthesis of a series of C-10 trifluoromethyl ethers of artemisinin has been achieved from key bromide I, itself carried out in two steps from artemisinin. The substitution of I with methanol, ethanol, or succinic acid allowed the access of C-10 CF3 analogs of β-artemether, β-arteether, or artesunate, resp., in good yields (up to 89%). The presence of the CF3 group at C-10 of artemisinin clearly increased the chem. stability under simulated stomach acid conditions. For example, the CF3 analog of arteether was found to be around 45 times more stable than arteether itself. The influence of the CF3 moiety on biol. activity was also highlighted. CF3 analogs of artemether and arteether exhibited a high in vivo antimalarial activity on mice infected with Plasmodium berghei NK173, with a complete clearance of the parasitemia during the entire observation period (25 days).(c) Bgu, J.-P.; Bonnet-Delpon, D. Antimalarial fluoroartimisinins: increased metabolic and chemical stability. Fluorine in Medicinal Chemistry and Chemical Biology 2009, 141– 163, DOI: 10.1002/9781444312096.ch6 .(d) Njokah, M. J.; Kang’ethe, J. N.; Kinyua, J.; Kariuki, D.; Kimani, F. T. In vitro selection of Plasmodium falciparum Pfcrt and Pfmdr1 variants by artemisinin. Malar. J. 2016, 15, 381, DOI: 10.1186/s12936-016-1443-y[Crossref], [PubMed], [CAS], Google Scholar105dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhslarsr%252FI&md5=3dd5a8a4bdb05d82af33b6735bd45b4dIn vitro selection of Plasmodium falciparum Pfcrt and Pfmdr1 variants by artemisininNjokah, Muturi J.; Kang'ethe, Joseph N.; Kinyua, Johnson; Kariuki, Daniel; Kimani, Francis T.Malaria Journal (2016), 15 (), 381/1-381/9CODEN: MJAOAZ; ISSN:1475-2875. (BioMed Central Ltd.)Background: Anti-malarial drugs are the major focus in the prevention and treatment of malaria. Artemisinin-based combination therapy (ACT) is the WHO recommended first-line treatment for Plasmodium falciparum malaria across the endemic world. Also ACT is increasingly relied upon in treating Plasmodium vivax malaria where chloroquine is failing. The emergence of artemisinin drug-resistant parasites is a serious threat faced by global malaria control programs. Therefore, the success of treatment and intervention strategies is highly pegged on understanding the genetic basis of resistance. Methods: Here, resistance in P. falciparum was generated in vitro for artemisinin to produce levels above clin. relevant concns. in vivo, and the mol. haplotypes investigated. Genomic DNA was extd. using the QIAamp mini DNA kit. DNA sequences of Pfk13, Pfcrt and Pfmdr1 genes were amplified by PCR and the amplicons were successfully sequenced. Single nucleotide polymorphisms were traced by std. bidirectional sequencing and reading the transcripts against wild-type sequences in Codon code Aligner Version 5.1 and NCBI blast. Results: Exposure of parasite strains D6 and W2 to artemisinin resulted in a decrease in parasite susceptibility to artemisinin (W2 and D6) and lumefantrine (D6 only). The parasites exhibited elevated IC50s to multiple artemisinins, with >twofold resistance to artemisinin; however, the resistance index obtained with std. methods was noticeably less than expected for parasite lines recovered from 50 μg/mL 48 h drug pressure. The change in parasite susceptibility was assocd. with Pfmdr-185K mutation, a mutation never reported before. The Pfcrt-CVMNK genotype (Pfcrt codons 72-76) was retained and notably, the study did not detect any polymorphisms reported to reduce P. falciparum susceptibility in vivo in the coding sequences of the Pfk13 gene. Discussion: This data demonstrate that P. falciparum has the capacity to develop resistance to artemisinin derivs. in vitro and that this phenotype is achieved by mutations in Pfmdr1, the genetic changes that are also underpinning lumefantrine resistance. This finding is of practical importance, because artemisinin drugs in Kenya are used in combination with lumefantrine for the treatment of malaria. Conclusion: Artemisinin resistance phenotype as has been shown in this work, is a decrease in parasites susceptibility to artemisinin derivs. together with the parasite's ability to recover from drug-induced dormancy after exposure to drug dosage above the in vivo clin. concns. The study surmises that Pfmdr1 may play a role in the anti-malarial activity of artemisinin.
- 106Elkeles, R. Fibrates: old drugs with a new role in type 2 diabetes prevention?. Br. J. Diabetes Vasc. Dis. 2011, 11, 4– 9, DOI: 10.1177/1474651410397245
- 107Pirat, C.; Farce, A.; Lebegue, N.; Renault, N.; Furman, C.; Millet, R.; Yous, S.; Speca, S.; Berthelot, P.; Desreumaux, P.; Chavatte, P. Targeting peroxisome proliferator-activated receptors (PPARs): development of modulators. J. Med. Chem. 2012, 55, 4027– 4061, DOI: 10.1021/jm101360s[ACS Full Text], [CAS], Google Scholar107https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XpsVOruw%253D%253D&md5=f32ec6b6d9f353199a56345f8cfc475cTargeting Peroxisome Proliferator-Activated Receptors (PPARs): Development of ModulatorsPirat, Celine; Farce, Amaury; Lebegue, Nicolas; Renault, Nicolas; Furman, Christophe; Millet, Regis; Yous, Said; Speca, Silvia; Berthelot, Pascal; Desreumaux, Pierre; Chavatte, PhilippeJournal of Medicinal Chemistry (2012), 55 (9), 4027-4061CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)This review covers the rapid progress in the functional anal. of the Peroxisome Proliferator-Activated Receptors (PPARs), which has led to a greater understanding of these receptors and has established them as mol. targets for the development of drugs against metabolic diseases. Natural and synthetic ligands for the three subtypes PPARalpha, PPARgamma and PPARbeta/delta, are reported: agonists or antagonists, partial or selective PPARs modulators (SPPARMs), dual agonists and pan-PPARalpha,gamma,beta/delta agonists. We conclude with the future of PPARs ligands research and the emergence of new hybrid compds. of the multitarget drug genre with a particular interest in the treatment of chronic inflammation.
- 108(a) Asaki, T.; Aoki, T.; Hamamoto, T.; Sugiyama, Y.; Ohmachi, S.; Kuwabara, K.; Murakami, K.; Todo, M. Structure-activity studies on 1,3-dioxane-2-carboxylic acid derivatives, a novel class of subtype-selective peroxisome proliferator-activated receptor δ. (PPARα) agonists. Bioorg. Med. Chem. 2008, 16, 981– 994, DOI: 10.1016/j.bmc.2007.10.007[Crossref], [PubMed], [CAS], Google Scholar.108ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsF2jsrc%253D&md5=c774d3d4fff3c548faeb114dc1c2dc9bStructure-activity studies on 1,3-dioxane-2-carboxylic acid derivatives, a novel class of subtype-selective peroxisome proliferator-activated receptor α (PPARα) agonistsAsaki, Tetsuo; Aoki, Tomiyoshi; Hamamoto, Taisuke; Sugiyama, Yukiteru; Ohmachi, Shinji; Kuwabara, Kenji; Murakami, Kohji; Todo, MakotoBioorganic & Medicinal Chemistry (2008), 16 (2), 981-994CODEN: BMECEP; ISSN:0968-0896. (Elsevier Ltd.)A series of 1,3-dioxane carboxylic acid derivs. was synthesized and evaluated for human PPAR transactivation activity. Structure-activity relationships on the phenyloxazole moiety of the lead compd. I revealed that the introduction of small hydrophobic substituents at the 4-position of the terminal Ph ring increased the PPARα agonist activity, and that the oxazole heterocycle was essential to the maintenance of both potency and PPARα subtype-selectivity. This investigation led to the identification of highly potent and selective human PPARα agonists (II and III). In KK-Ay type 2 diabetic mice, these compds. significantly lowered plasma triglyceride and very-low-d. plus low-d. lipoprotein cholesterol levels while simultaneously raising HDL cholesterol levels. The results suggest that highly potent and subtype-selective PPARα agonists will be promising drugs for the treatment of metabolic disorders in type 2 diabetes.(b) Aoki, T.; Asaki, T.; Hamamoto, T.; Sugiyama, Y.; Ohmachi, S.; Kuwabara, K.; Murakami, K.; Todo, M. Discovery of a novel class of 1,3-dioxane-2-carboxylic acid derivatives as subtype-selective peroxisome proliferator-activated receptor δ (PPARα) agonists. Bioorg. Med. Chem. Lett. 2008, 18, 2128– 2132, DOI: 10.1016/j.bmcl.2008.01.086[Crossref], [PubMed], [CAS], Google Scholar108bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXjtlymu7w%253D&md5=b2947fecc4c870ad7449fbf1219dd856Discovery of a novel class of 1,3-dioxane-2-carboxylic acid derivatives as subtype-selective peroxisome proliferator-activated receptor α (PPARα) agonistsAoki, Tomiyoshi; Asaki, Tetsuo; Hamamoto, Taisuke; Sugiyama, Yukiteru; Ohmachi, Shinji; Kuwabara, Kenji; Murakami, Kohji; Todo, MakotoBioorganic & Medicinal Chemistry Letters (2008), 18 (6), 2128-2132CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)A series of 1,3-dioxane-2-carboxylic acid derivs. was synthesized and evaluated for agonist activity at human peroxisome proliferator-activated receptor (PPAR) subtypes. Structure-activity relationship studies led to the identification of compd. I as a potent PPARα agonist with high subtype selectivity at human receptor subtypes. This compd. exhibited a substantial hypolipidemic effect in type 2 diabetic KK-Ay mice.
- 109(a) Tschierske, C.; Kshler, H.; Zaschke, H.; Kleinpete, E. The anomeric effect of the carboethoxy group in oxygen and sulfur containing heterocycles. Tetrahedron 1989, 45, 6987– 6998, DOI: 10.1016/S0040-4020(01)89165-1[Crossref], [CAS], Google Scholar.109ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3cXitlCltbk%253D&md5=ce81459cc5ab840783c89752d7ffb4d5The anomeric effect of the carboethoxy group in oxygen and sulfur containing heterocyclesTschierske, C.; Koehler, H.; Zaschke, H.; Kleinpeter, E.Tetrahedron (1989), 45 (22), 6987-98CODEN: TETRAB; ISSN:0040-4020.The anomeric effect of the carboethoxy substituents and the ring oxygen in 1,3-dioxane- and 1,3-oxathiane-2-carboxylates has been estd. in low polar solvents by including empirical correlation factor α to be 4 kJ/mol. The conformational energies of the 2-carboethoxy substituent fit the parabolic Zefirov dependence on the solvent dielec. const. in the 1,3-dioxane-2-carboxylates. Deviations in the case of the 1,3-oxathiane-2-carboxylates indicate a second conformational equil. involved which is the rotation of the COOR substituent about the exocyclic bond to the heterocyclic ring. Preferred rotamers have been assigned and discussed in terms of special πCO/3d(S) orbital interactions.(b) Harabe, T.; Matsumoto, T.; Shioiri, T. Conformational analysis and selective hydrolysis of 2,5-disubstituted-1,3-dioxane-2-carboxylic acid esters. Tetrahedron Lett. 2007, 48, 1443– 1446, DOI: 10.1016/j.tetlet.2006.12.117[Crossref], [CAS], Google Scholar.109bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXht1ajtLc%253D&md5=49783bf4aad64b69935b6641666d71c4Conformational analysis and selective hydrolysis of 2,5-disubstituted-1,3-dioxane-2-carboxylic acid estersHarabe, Tetsuji; Matsumoto, Takatoshi; Shioiri, TakayukiTetrahedron Letters (2007), 48 (8), 1443-1446CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)5-Alkyl-2-methyl-2-carbomethoxy-1,3-dioxanes were found to have a cis preferential configuration in the equil. state, and the ester hydrolysis rate of the trans-isomers was faster than that of the cis-isomers. Conformational anal. and charge calcn. of the carbomethoxy group in both dioxanes elucidated this selectivity.(c) Harabe, T.; Matsumoto, T.; Shioiri, T. Esters of 2,5-multisubstituted-1,3-dioxane-2-carboxylic acid: their conformational analysis and selective hydrolysis. Tetrahedron 2009, 65, 4044– 4052, DOI: 10.1016/j.tet.2009.02.076[Crossref], [CAS], Google Scholar109chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXkslOqtb0%253D&md5=99f2b4cd44cd7148864d5bb7e9b496b5Esters of 2,5-multisubstituted-1,3-dioxane-2-carboxylic acid: their conformational analysis and selective hydrolysisHarabe, Tetsuji; Matsumoto, Takatoshi; Shioiri, TakayukiTetrahedron (2009), 65 (20), 4044-4052CODEN: TETRAB; ISSN:0040-4020. (Elsevier Ltd.)The carbomethoxy group at the C2 position of the 2,5-multisubstituted 1,3-dioxanes prefers the axial conformation rather than the equatorial one due to an anomeric effect. The trans isomers of the 5-monosubstituted compds. are more selectively hydrolyzed than the cis isomers. Based on the calcd. results, hydrolysis to the trans isomers is attributed to the larger carbonyl charges of the trans than those of the cis isomers. The anomeric and homoanomeric effects will explain the axial preference of the carbomethoxy group and selective hydrolysis to the trans isomers. Furthermore, the calcd. stability between the cis and trans isomers is in good agreement with the exptl. results in the equil. state.
- 110(a) Zaware, P.; Shah, S. R.; Pingali, H.; Makadia, P.; Thube, B.; Pola, S.; Patel, D.; Priyadarshini, P.; Suthar, D.; Shah, M.; Jamili, J.; Sairam, K. V.; Giri, S.; Patel, L.; Patel, H.; Sudani, H.; Patel, H.; Jain, M.; Patel, P.; Bahekar, R. Modulation of PPAR subtype selectivity. Part 2: Transforming PPARα/δ dual agonist into a selective PPAR agonist through bioisosteric modification. Bioorg. Med. Chem. Lett. 2011, 21, 628– 632, DOI: 10.1016/j.bmcl.2010.12.032[Crossref], [PubMed], [CAS], Google Scholar.110ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXktVKrtg%253D%253D&md5=82697a3e007c0ea5344cf68a1273f904Modulation of PPAR subtype selectivity. Part 2: Transforming PPARα/γ dual agonist into α selective PPAR agonist through bioisosteric modificationZaware, Pandurang; Shah, Shailesh R.; Pingali, Harikishore; Makadia, Pankaj; Thube, Baban; Pola, Suresh; Patel, Darshit; Priyadarshini, Priyanka; Suthar, Dinesh; Shah, Maanan; Jamili, Jeevankumar; Sairam, Kalapatapu V. V. M.; Giri, Suresh; Patel, Lala; Patel, Harilal; Sudani, Hareshkumar; Patel, Hiren; Jain, Mukul; Patel, Pankaj; Bahekar, RajeshBioorganic & Medicinal Chemistry Letters (2011), 21 (2), 628-632CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A novel series of oxime contg. benzyl-1,3-dioxane-r-2-carboxylic acid derivs. (6a-k) were designed as selective PPARα agonists, through bioisosteric modification in the lipophilic tail region of PPARα/γ dual agonist. Some of the test compds. (6a, 6b, 6c and 6f) showed high selectivity towards PPARα over PPARγ in vitro. Further, highly potent and selective PPARα agonist 6c (I) exhibited significant antihyperglycemic and antihyperlipidemic activity in vivo, along with its improved pharmacokinetic profile. Favorable in-silico interaction of 6c with PPARα binding pocket correlate its in vitro selectivity profile toward PPARα over PPARγ. Together, these results confirm discovery of novel series of oxime based selective PPARα agonists for the safe and effective treatment of various metabolic disorders.(b) Pingali, H.; Jain, M.; Shah, S.; Patil, P.; Makadia, P.; Zaware, P.; Sairam, K. V.; Jamili, J.; Goel, A.; Patel, M.; Patel, P. Modulation of PPAR receptor subtype selectivity of the ligands: Aliphatic chain vs aromatic ring as a spacer between pharmacophore and the lipophilic moiety. Bioorg. Med. Chem. Lett. 2008, 18, 6471– 6475, DOI: 10.1016/j.bmcl.2008.10.062[Crossref], [PubMed], [CAS], Google Scholar110bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsVWjsL7L&md5=cafedfdc3c475cb6a2eb8f8752d896d5Modulation of PPAR receptor subtype selectivity of the ligands: Aliphatic chain vs aromatic ring as a spacer between pharmacophore and the lipophilic moietyPingali, Harikishore; Jain, Mukul; Shah, Shailesh; Patil, Pravin; Makadia, Pankaj; Zaware, Pandurang; Sairam, Kalapatapu V. V. M.; Jamili, Jeevankumar; Goel, Ashish; Patel, Megha; Patel, PankajBioorganic & Medicinal Chemistry Letters (2008), 18 (24), 6471-6475CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)Oxazole contg. glycine and oximinobutyric acid derivs. were synthesized as PPARα agonists by incorporating polymethylene spacer as a replacement of commonly used phenylene group that connects the acidic head with lipophilic tail. I was found to be a selective and potent PPARα agonist. Further 1,3-dioxane-2-carboxylic acid deriv. II was synthesized by replacing the tetramethylene spacer of NS-220, a selective PPARα agonist with phenylene group and found to exhibit PPARα/γ dual agonism. These results suggest that compds. possessing polymethylene spacer between pharmacophore and lipophilic tail exhibit predominantly PPARα agonism whereas those with an arom. phenylene spacer shows PPARα/γ dual agonism.
- 111LeMahieu, R. A.; Carson, M.; Kierstead, R. W.; Fern, L. M.; Grunberg, E. Glycoside cleavage reactions on erythromycin A. Preparation of erythronolide A. J. Med. Chem. 1974, 17, 953– 956, DOI: 10.1021/jm00255a009[ACS Full Text], [CAS], Google Scholar111https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE2MXptQ%253D%253D&md5=55aad7d5aff5095162f5a240af7e5e95Glycoside cleavage reactions on erythromycin A. Preparation of erythronolide ALeMahieu, Ronald A.; Carson, Mathew; Kierstead, Richard W.; Fern, Lucy M.; Grunberg, E.Journal of Medicinal Chemistry (1974), 17 (9), 953-6CODEN: JMCMAR; ISSN:0022-2623.Selective cleavage of erythromycin A oxime [13127-18-9] by HCl-MeOH, followed by treatment with HNO2 gave 5-O-desosaminylerythronolide A (I) [53066-32-3]. Erythromycin A oxime was converted to the N-oxide [53317-21-8], which was subjected to pyrolysis, hydrolytic cleavage, and treatment with HNO2 to give erythronolide A (II) [26754-37-0]. I and II and intermediate compds. and derivs. had little or no antibacterial activity in vitro or in vivo. The activity in relation to the presence of sugar substituents was discussed.
- 112(a) Martin, R.; Plancq, B.; Gavelle, O.; Wagner, B.; Fischer, H.; Bendels, S.; Müller, K. Remote modulation of amine basicity by a phenylsulfone and a phenylthio group. ChemMedChem 2007, 2, 285– 287, DOI: 10.1002/cmdc.200600265[Crossref], [PubMed], [CAS], Google Scholar.112ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXmtVWqtLk%253D&md5=1e5681e5549ca7fc205493c7db96262bRemote modulation of amine basicity by a phenylsulfone and a phenylthio groupMartin, Rainer E.; Plancq, Baptiste; Gavelle, Olivier; Wagner, Bjorn; Fischer, Holger; Bendels, Stefanie; Muller, KlausChemMedChem (2007), 2 (3), 285-287CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)A series of Ph sulfones and phenylthioamines was studied with respect to their pKa values in water under std. conditions.(b) Morgenthaler, M.; Schweizer, E.; Hoffmann-Röder, A.; Benini, F.; Martin, R.; Jaeschke, G.; Wagner, B.; Fischer, H.; Bendels, S.; Zimmerli, D.; Schneider, J.; Diederich, F.; Kansy, M.; Müller, K. Predicting and tuning physicochemical properties in lead optimization: amine basicities. ChemMedChem 2007, 2, 1100– 1115, DOI: 10.1002/cmdc.200700059[Crossref], [PubMed], [CAS], Google Scholar112bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXpsFemsbY%253D&md5=478b70744312c01d3a43cf435d9598dePredicting and tuning physicochemical properties in lead optimization: amine basicitiesMorgenthaler, Martin; Schweizer, Eliane; Hoffmann-Roder, Anja; Benini, Fausta; Martin, Rainer E.; Jaeschke, Georg; Wagner, Bjorn; Fischer, Holger; Bendels, Stefanie; Zimmerli, Daniel; Schneider, Josef; Diederich, Francois; Kansy, Manfred; Muller, KlausChemMedChem (2007), 2 (8), 1100-1115CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. This review describes simple and useful concepts for predicting and tuning the pKa values of basic amine centers, a crucial step in the optimization of phys. and ADME properties of many lead structures in drug-discovery research. The article starts with a case study of tricyclic thrombin inhibitors featuring a tertiary amine center with pKa values that can be tuned over a wide range, from the usual value of around 10 to below 2 by (remote) neighboring functionalities commonly encountered in medicinal chem. Next, the changes in pKa of acyclic and cyclic amines upon substitution by fluorine, oxygen, nitrogen, and sulfur functionalities, as well as carbonyl and carboxyl derivs. are systematically analyzed, leading to the derivation of simple rules for pKa prediction. Electronic and stereoelectronic effects in cyclic amines are discussed, and the emerging computational methods for pKa predictions are briefly surveyed. The rules for tuning amine basicities should not only be of interest in drug-discovery research, but also to the development of new crop-protection agents, new amine ligands for organometallic complexes, and in particular, to the growing field of amine-based organocatalysis.
- 113Lenci, E.; Calugi, L.; Trabocchi, A. Occurrence of morpholine in central nervous system drug discovery. ACS Chem. Neurosci. 2021, 12, 378– 390, DOI: 10.1021/acschemneuro.0c00729[ACS Full Text], [CAS], Google Scholar113https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhtlWksrk%253D&md5=b06e6e857730c2648abc38bcbfe42a44Occurrence of Morpholine in Central Nervous System Drug DiscoveryLenci, Elena; Calugi, Lorenzo; Trabocchi, AndreaACS Chemical Neuroscience (2021), 12 (3), 378-390CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)Developing drugs for the central nervous system (CNS) requires fine chem. modifications, as a strict balance between size and lipophilicity is necessary to improve the permeability through the blood-brain barrier (BBB). In this context, morpholine and its analogs represent valuable heterocycles, due to their conformational and physicochem. properties. In fact, the presence of a weak basic nitrogen atom and of an oxygen atom at the opposite position provides a peculiar pKa value and a flexible conformation to the ring, thus allowing it to take part in several lipophilic-hydrophilic interactions, and to improve blood soly. and brain permeability of the overall structure. In CNS-active compds., morpholines are used (1) to enhance the potency through mol. interactions, (2) to act as a scaffold directing the appendages in the correct position, and (3) to modulate pharmacokinetic/pharmacodynamic (PK/PD) properties. In this perspective, selected morpholine-contg. CNS drug candidates are discussed to reveal the active pharmacophores accountable for the (1) modulation of receptors involved in mood disorders and pain, (2) bioactivity toward enzymes and receptors responsible for neurodegenerative diseases, and (3) inhibition of enzymes involved in the pathol. of CNS tumors. The medicinal chem./pharmacol. activity of morpholine derivs. is discussed, in the effort to highlight the importance of morpholine ring interactions in the active site of different targets, particularly reporting binding features retrieved from PDB data, when available.
- 114(a) Hale, J. L.; Mills, S. G.; MacCoss, M.; Shah, S. K.; Qi, H.; Mathre, D. J.; Cascieri, M. A.; Sadowski, S.; Strader, C. D.; MacIntyre, D. E.; Metzger, J. M. 2(S)-((3,5-Bis(trifluoromethyl)benzyl)-oxy)-3(S)-phenyl-4-((3-oxo-1,2,4-triazol-5-yl)methyl)morpholine (1): a potent, orally active, morpholine-based human neurokinin-1 receptor antagonist. J. Med. Chem. 1996, 39, 1760– 1762, DOI: 10.1021/jm950654w[ACS Full Text.], [CAS], Google Scholar114ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XitVaqsbg%253D&md5=8715401a42036191a1821411e8a646732(S)-((3,5-Bis(trifluoromethyl)benzyl)oxy)-3(S)-phenyl-4-((3-oxo-1,2,4-triazol-5-yl)methyl)morpholine): A Potent, Orally Active, Morpholine-Based Human Neurokinin-1 Receptor AntagonistHale, Jeffrey J.; Mills, Sander G.; MacCoss, Malcolm; Shah, Shrenik K.; Qi, Hongbo; Mathre, David J.; Cascieri, Margaret A.; Sadowski, Sharon; Strader, Catherine D.; et al.Journal of Medicinal Chemistry (1996), 39 (9), 1760-2CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The title compd., L-742694, (I) was prepd. from by the reaction of the corresponding morpholine deriv. with N-(methoxycarbonyl)-2-chloroacetamidrazone followed by thermal ring closure. Analogs of I were also prepd. I and the other morpholines represented a novel class of human neurokinin-1 receptor antagonists. Further, I is a potent, orally active member of this class that might be an important tool in the study of neurokinin pharmacol.(b) Ladduwahetty, T.; Baker, R.; Cascieri, M. A.; Chambers, M. S.; Haworth, K.; Keown, L. E.; MacIntyre, D. E.; Metzger, J. M.; Owen, S.; Rycroft, W.; Sadowski, S.; Seward, E. M.; Shepheard, S. L.; Swain, C. J.; Tattersall, F. D.; Watt, A. P.; Williamson, D. W.; Hargreaves, R. J. N-Heteroaryl-2-phenyl-3-(benzyloxy)piperidines: a novel class of potent orally active human NK1 antagonists. J. Med. Chem. 1996, 39, 2907– 2914, DOI: 10.1021/jm9506534[ACS Full Text.], [CAS], Google Scholar114bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XjvVejsbs%253D&md5=afa2309c25cebd3a418f9aeb1ce73ce9N-Heteroaryl-2-phenyl-3-(benzyloxy)piperidines: A Novel Class of Potent Orally Active Human NK1 AntagonistsLadduwahetty, T.; Baker, R.; Cascieri, M. A.; Chambers, M. S.; Haworth, K.; Keown, L. E.; MacIntyre, D. E.; Metzger, J. M.; Owen, S.; et al.Journal of Medicinal Chemistry (1996), 39 (15), 2907-2914CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The prepn. of a series of N-(heteroarylmethyl)-2-phenyl-3-[[3,5-bis(trifluoromethyl)phenyl]methoxy]piperidine I (R = 2-furanylmethyl, 4-oxazolylmethyl, 5-tetrazolylmethyl, etc.) as human NK1 antagonists was described. Two of the compds., 3-[{(2S,3S)-3-(((3,5-bis(trifluoromethyl)phenyl)methyl)oxy)-2-phenylpiperidino}methyl]-1,2,4-triazole and 5-[{(2S,3S)-3-(((3,5-bis(trifluoromethyl)phenyl)methyl)oxy)-2-phenylpiperidino}methyl]-1,2,4-triazol-3-one (II), in particular, are orally bioavailable and exhibited significant improvements in potency, both in vitro and in vivo, over the lead (carboxamidomethyl)piperidine ether L 736281. Rat liver microsome studies on a selected no. of compds. from this series show the triazolone heterocycle to be considerably more stable than the others. Furthermore, II was profiled in a no. of assays that may be predictive of the clin. utility of substance P antagonists.(c) Chen, S.; Lu, M.; Liu, D.; Yang, L.; Yi, C.; Ma, L.; Zhang, H.; Liu, Q.; Frimurer, T. M.; Wang, M.-W.; Schwartz, T. W.; Stevens, R. C.; Wu, B.; Wüthrich, K.; Zhao, Q. Human substance P receptor binding mode of the antagonist drug aprepitant by NMR and crystallography. Nat. Commun. 2019, 10, 638, DOI: 10.1038/s41467-019-08568-5[Crossref], [PubMed], [CAS], Google Scholar.114chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXns1Crurg%253D&md5=e00d2059f8f51f3ce8b20d43ea874217Human substance P receptor binding mode of the antagonist drug aprepitant by NMR and crystallographyChen, Shuanghong; Lu, Mengjie; Liu, Dongsheng; Yang, Lingyun; Yi, Cuiying; Ma, Limin; Zhang, Hui; Liu, Qing; Frimurer, Thomas M.; Wang, Ming-Wei; Schwartz, Thue W.; Stevens, Raymond C.; Wu, Beili; Wuthrich, Kurt; Zhao, QiangNature Communications (2019), 10 (1), 638CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)Neurokinin 1 receptor (NK1R) has key regulating functions in the central and peripheral nervous systems, and NK1R antagonists such as aprepitant have been approved for treating chemotherapy-induced nausea and vomiting. However, the lack of data on NK1R structure and biochem. has limited further drug development targeting this receptor. Here, we combine NMR spectroscopy and X-ray crystallog. to provide dynamic and static characterization of the binding mode of aprepitant in complexes with human NK1R variants. The 19F-NMR showed a slow off-rate in the binding site, where aprepitant occupies multiple substates that exchange with frequencies in the millisecond range. The environment of the bound ligand is affected by the amino acid in position 2.50, which plays a key role in ligand binding and receptor signaling in class A GPCRs. Crystal structures now reveal how receptor signaling relates to the conformation of the conserved NP7.50xxY motif in transmembrane helix VII.(d) Gangula, S.; Elati, C. R.; Mudunuru, S. V.; Nardela, A.; Dongamanti, A.; Bhattacharya, A.; Bandichhor, R. Synthesis of all enantiomerically pure diastereomers of aprepitant. Synth. Commun. 2010, 40, 2254– 2268, DOI: 10.1080/00397910903221084[Crossref], [CAS], Google Scholar114dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXosFCrs7Y%253D&md5=6871efa0178f38e8da50754bcd219269Synthesis of All Enantiomerically Pure Diastereomers of AprepitantGangula, Srinivas; Elati, Chandrashekhar R.; Mudunuru, Satish Varma; Nardela, Anitha; Dongamanti, Ashok; Bhattacharya, Apurba; Bandichhor, RakeshwarSynthetic Communications (2010), 40 (15), 2254-2268CODEN: SYNCAV; ISSN:0039-7911. (Taylor & Francis, Inc.)Syntheses of all eight enantiomerically pure diastereomers of aprepitant, I, and assignment of abs. configuration at newly generated stereocenters by NMR and x-ray crystallog. anal. (no data) were achieved.
- 115Hale, J. J.; Mills, S. G.; MacCoss, M.; Dorn, C. P.; Finke, P. E.; Budhu, R. J.; Reamer, R. A.; Huskey, S. W.; Luffer-Atlas, D.; Dean, B. J.; McGowan, E. M.; Feeney, W. P.; Chiu, S. L.; Cascieri, M. A.; Chicchi, G. G.; Kurtz, M. M.; Sadowski, S.; Ber, E.; Tattersall, F. D.; Rupniak, N. M.; Williams, A. R.; Rycroft, W.; Hargreaves, R.; Metzger, J. M.; MacIntyre, D. E. Phosphorylated morpholine acetal human neurokinin-1 receptor antagonists as water-soluble prodrugs. J. Med. Chem. 2000, 43, 1234– 1241, DOI: 10.1021/jm990617v[ACS Full Text], [CAS], Google Scholar115https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXht1yjtrc%253D&md5=8cabf4d88128125abb0f75fbe572eae3Phosphorylated Morpholine Acetal Human Neurokinin-1 Receptor Antagonists as Water-Soluble ProdrugsHale, Jeffrey J.; Mills, Sander G.; MacCoss, Malcolm; Dorn, Conrad P.; Finke, Paul E.; Budhu, Richard J.; Reamer, Robert A.; Huskey, Su-Er W.; Luffer-Atlas, Debra; Dean, Brian J.; McGowan, Erin M.; Feeney, William P.; Chiu, Shuet-Hing Lee; Cascieri, Margaret A.; Chicchi, Gary G.; Kurtz, Marc M.; Sadowski, Sharon; Ber, Elzbieta; Tattersall, F. David; Rupniak, Nadia M. J.; Williams, Angela R.; Rycroft, Wayne; Hargreaves, Richard; Metzger, Joseph M.; MacIntyre, D. EuanJournal of Medicinal Chemistry (2000), 43 (6), 1234-1241CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The regioselective dibenzylphosphorylation of I (R = H) followed by catalytic redn. in the presence of N-methyl-D-glucamine afforded 2-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(1-phosphoryl-3-oxo-4H,-1,2,4-triazol-5-yl)methylmorpholine, bis(N-methyl-D-glucamine) salt, II (I, R = PO3H2, bis(N-methyl-D-glucamine) salt ). Incubation in rat, dog, and human plasma and in human hepatic subcellular fractions in vitro indicated that conversion to I would be expected to occur in vivo most readily in humans during hepatic circulation. Conversion of I to II occurred rapidly in vivo in the rat and dog with the levels of II being undetectable within 5 min after 1 and 8 mg/kg doses i.v. in the rat and within 15 min after 0.5, 2, and 32 mg/kg doses i.v. in the dog. II has a 10-fold lower affinity for the human NK-1 receptor as compared to I, but it is functionally equiv. to I in preclin. models of NK-1-mediated inflammation in the guinea pig and cisplatin-induced emesis in the ferret, indicating that II acts as a prodrug of I. Based in part on these data, II was identified as a novel, water-sol. prodrug of the clin. candidate I suitable for i.v. administration in humans.
- 116(a) Fuller, N. O.; Hubbs, J. J.; Austin, W. F.; Creaser, S. P.; McKee, T. D.; Loureiro, R. M.; Tate, B.; Xia, W.; Ives, J. L.; Findeis, M. A.; Bronk, B. S. Initial optimization of a new series of γ-secretase modulators derived from a triterpene glycoside. ACS Med. Chem. Lett. 2012, 3, 908– 913, DOI: 10.1021/ml300256p[ACS Full Text.], [CAS], Google Scholar116ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xht1yhsLjO&md5=998a73e5df368087af6c75038cd74eaaInitial Optimization of a New Series of γ-Secretase Modulators Derived from a Triterpene GlycosideFuller, Nathan O.; Hubbs, Jed L.; Austin, Wesley F.; Creaser, Steffen P.; McKee, Timothy D.; Loureiro, Robyn M. B.; Tate, Barbara; Xia, Weiming; Ives, Jeffrey L.; Findeis, Mark A.; Bronk, Brian S.ACS Medicinal Chemistry Letters (2012), 3 (11), 908-913CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)The discovery of a new series of γ-secretase modulators is disclosed. Starting from a triterpene glycoside γ-secretase modulator that gave a very low brain-to-plasma ratio, initial SAR and optimization involved replacement of a pendant sugar with a series of morpholines. This modification led to two compds. with significantly improved central nervous system (CNS) exposure.(b) Hubbs, J. L.; Fuller, N. O.; Austin, W. F.; Shen, R.; Creaser, S. P.; McKee, T. D.; Loureiro, R. M.; Tate, B.; Xia, W.; Ives, J.; Bronk, B. S. Optimization of a natural product-based class of γ-secretase modulators. J. Med. Chem. 2012, 55, 9270– 9282, DOI: 10.1021/jm300976b[ACS Full Text.], [CAS], Google Scholar116bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsVGqtLfO&md5=3a826577aa836f3235a4b61468fa0c0eOptimization of a Natural Product-Based Class of γ-Secretase ModulatorsHubbs, Jed L.; Fuller, Nathan O.; Austin, Wesley F.; Shen, Ruichao; Creaser, Steffen P.; McKee, Timothy D.; Loureiro, Robyn M. B.; Tate, Barbara; Xia, Weiming; Ives, Jeffrey; Bronk, Brian S.Journal of Medicinal Chemistry (2012), 55 (21), 9270-9282CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A series of triterpene-based γ-secretase modulators is optimized. An acetate present at the C24 position of the natural product was replaced with either carbamates or ethers to provide compds. with better metabolic stability. With one of those pharmacophores in place at C24, morpholines or carbamates were installed at the C3 position to refine the physicochem. properties of the analogs. This strategy gave compds. with low clearance and good distribution into the central nervous system (CNS) of CD-1 mice. Two of these compds., I and II, were tested for a pharmacodynamic effect and exhibited statistically significant lowering of brain Aβ42 levels.(c) Loureiro, R. M.; Dumin, J. A.; McKee, T. D.; Austin, W. F.; Fuller, N. O.; Hubbs, J. L.; Shen, R.; Jonker, J.; Ives, J.; Bronk, B. S.; Tate, B. Efficacy of SPI-1865, a novel gamma-secretase modulator, in multiple rodent models. Alzheimer's Res. Ther. 2013, 5, 19, DOI: 10.1186/alzrt173[Crossref], [CAS], Google Scholar.116chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXos1Oltbc%253D&md5=f452b63f5a006a1bd8f379c64e14f6a4Efficacy of SPI-1865, a novel gamma-secretase modulator, in multiple rodent modelsLoureiro, Robyn M.; Dumin, Jo Ann; McKee, Timothy D.; Austin, Wesley F.; Fuller, Nathan O.; Hubbs, Jed L.; Shen, Ruichao; Jonker, Jeff; Ives, Jeff; Bronk, Brian S.; Tate, BarbaraAlzheimer's Research & Therapy (2013), 5 (2), 19CODEN: ARTLCD; ISSN:1758-9193. (BioMed Central Ltd.)Introduction: Modulation of the gamma-secretase enzyme, which reduces the prodn. of the amyloidogenic Aβ42 peptide while sparing the prodn. of other Aβ species, is a promising therapeutic approach for the treatment of Alzheimer's disease. Satori has identified a unique class of small mol. gamma-secretase modulators (GSMs) capable of decreasing Aβ42 levels in cellular and rodent model systems. The compd. class exhibits potency in the nM range in vitro and is selective for lowering Aβ42 and Aβ38 while sparing Aβ40 and total Aβ levels. In vivo , a compd. from the series, SPI-1865, demonstrates similar pharmacol. in wild-type CD1 mice, Tg2576 mice and Sprague Dawley rats. Methods: Animals were orally administered either a single dose of SPI-1865 or dosed for multiple days. Aβ levels were measured using a sensitive plate-based ELISA system (MSD) and brain and plasma exposure of drug were assessed by LC/MS/MS. Results: In wild-type mice using either dosing regimen, brain Aβ42 and Aβ38 levels were decreased upon treatment with SPI-1865 and little to no statistically meaningful effect on Aβ40 was obsd., reflecting the changes obsd. in vitro. In rats, brain Aβ levels were examd. and similar to the mouse studies, brain Aβ42 and Aβ38 were lowered. Comparable changes were also obsd. in the Tg2576 mice, where Aβ levels were measured in brain as well as plasma and CSF. Conclusions: Taken together, these data indicate that SPI-1865 is orally bioavailable, brain penetrant, and effective at lowering Aβ42 in a dose responsive manner. With this unique profile, the class of compds. represented by SPI-1865 may be a promising new therapy for Alzheimer's disease.(d) Fuller, N. O.; Hubbs, J. L.; Austin, W. F.; Shen, R.; Ives, J.; Osswald, G.; Bronk, B. S. Optimization of a Kilogram-Scale Synthesis of a Potent Cycloartenol Triterpenoid-Derived γ-Secretase Modulator. Org. Process Res. Dev. 2014, 18, 683– 692, DOI: 10.1021/op500072b[ACS Full Text], [CAS], Google Scholar116dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXnt1CnsLs%253D&md5=a65f49d808414d1a4d77c1bd71730b00Optimization of a Kilogram-Scale Synthesis of a Potent Cycloartenol Triterpenoid-Derived γ-Secretase ModulatorFuller, Nathan O.; Hubbs, Jed L.; Austin, Wesley F.; Shen, Ruichao; Ives, Jeffrey; Osswald, Gerd; Bronk, Brian S.Organic Process Research & Development (2014), 18 (6), 683-692CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)This work describes the demonstration of a kilogram-scale synthesis of a γ-secretase modulator from a plant-sterol-derived starting material. Key to developing a synthetic route capable of delivering a kilogram of the target compd. I was the development of a four-reaction telescope process and a selective O-alkylation of a triol intermediate. These improvements enabled the successful delivery of kilogram-scale batches of API for preclin. development studies.
- 117(a) Kaneko, S.; Arai, M.; Uchida, T.; Harasaki, T.; Fukuoka, T.; Konosu, T. Synthesis and evaluation of N-substituted 1,4-oxazepanyl sordaricins as selective fungal EF-2 inhibitors. Bioorg. Med. Chem. Lett. 2002, 12, 1705– 1708, DOI: 10.1016/S0960-894X(02)00290-1[Crossref], [PubMed], [CAS], Google Scholar.117ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38Xktlyls70%253D&md5=390431805ed396121ad9de3fa2a4440cSynthesis and evaluation of N-substituted 1,4-oxazepanyl sordaricins as selective fungal EF-2 inhibitorsKaneko, Satoru; Arai, Masami; Uchida, Takuya; Harasaki, Tamako; Fukuoka, Takashi; Konosu, ToshiyukiBioorganic & Medicinal Chemistry Letters (2002), 12 (13), 1705-1708CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)Sordaricin analogs, e.g. I, possessing 6-methoxy-7-methyl-1,4-oxazepane moiety instead of the sugar part were synthesized and evaluated. It was found that N-substituents on the oxazepane ring had influence on biol. activity. In particular, N-(2-methylpropenyl) deriv. I exhibited potent in vitro antifungal activity. Furthermore, I maintained significant activity (MIC 0.25 μg/mL) against Candida albicans SANK51486 even in the presence of 20% horse serum.(b) Arai, M.; Harasaki, T.; Fukuoka, T.; Kaneko, S.; Konosu, T. Synthesis and evaluation of novel pyrrolidinyl sordaricin derivatives as antifungal agents. Bioorg. Med. Chem. Lett. 2002, 12, 2733– 2736, DOI: 10.1016/S0960-894X(02)00534-6[Crossref], [PubMed], [CAS], Google Scholar.117bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XmslGisb0%253D&md5=5f040aee26f60198e5164d1d36d87e6cSynthesis and evaluation of novel pyrrolidinyl sordaricin derivatives as antifungal agentsArai, Masami; Harasaki, Tamako; Fukuoka, Takashi; Kaneko, Satoru; Konosu, ToshiyukiBioorganic & Medicinal Chemistry Letters (2002), 12 (19), 2733-2736CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)N-Benzyl pyrrolidinyl sordaricin derivs. were synthesized in a stereocontrolled manner. These compds. maintained moderate antifungal activity against several pathogenic fungal strains. Their MIC values against Candida albicans were in the range of 0.25-2 μg/mL.(c) Serrano-Wu, M. H.; St. Laurent, D. R.; Chen, Y.; Huang, S.; Lam, K.-R.; Matson, J. A.; Mazzucco, C. E.; Stickle, T. M.; Tully, T. P.; Wong, H. S.; Vyas, D. M.; Balasubramanian, B. N. Sordarin oxazepine derivatives as potent antifungal agents. Bioorg. Med. Chem. Lett. 2002, 12, 2757– 2760, DOI: 10.1016/S0960-894X(02)00529-2[Crossref], [PubMed], [CAS], Google Scholar.117chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XmslGisLc%253D&md5=160441705dcaf29deaffb71e4787d47dSordarin Oxazepine Derivatives as Potent Antifungal AgentsSerrano-Wu, Michael H.; St. Laurent, Denis R.; Chen, Yijun; Huang, Stella; Lam, Kin-Ray; Matson, James A.; Mazzucco, Charles E.; Stickle, Terry M.; Tully, Thomas P.; Wong, Henry S.; Vyas, Dolatrai M.; Balasubramanian, Balu N.Bioorganic & Medicinal Chemistry Letters (2002), 12 (19), 2757-2760CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)The synthesis and biol. activity of sordarin oxazepine derivs., i.e. I, are described. The key step features a regioselective oxidn. of an unprotected triol followed by double reductive amination to afford the ring-closed products. The spectrum of antifungal activity for these novel derivs. includes coverage of Candida albicans, Candida glabrata, and Cryptococcus neoformans.(d) Serrano-Wu, M. H.; Laurent, D. R.S..; Carroll, T. M.; Dodier, M.; Gao, Q.; Gill, P.; Quesnelle, C.; Marinier, A.; Mazzucco, C. E.; Regueiro-Ren, A.; Stickle, T. M.; Wu, D.; Yang, H.; Yang, Z.; Zheng, M.; Zoeckler, M. E.; Vyas, D. M.; Balasubramanian, B. N. Identification of a broad-spectrum azasordarin with improved pharmacokinetic properties. Bioorg. Med. Chem. Lett. 2003, 13, 1419– 1423, DOI: 10.1016/S0960-894X(03)00161-6[Crossref], [PubMed], [CAS], Google Scholar.117dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXis1aqt74%253D&md5=db58c24820243710440e21dd1d43bbf9Identification of a broad-Spectrum azasordarin with improved pharmacokinetic propertiesSerrano-Wu, Michael H.; St. Laurent, Denis R.; Carroll, Tina M.; Dodier, Marco; Gao, Qi; Gill, Patrice; Quesnelle, Claude; Marinier, Anne; Mazzucco, Charles E.; Regueiro-Ren, Alicia; Stickle, Terry M.; Wu, Dedong; Yang, Hyekyung; Yang, Zheng; Zheng, Ming; Zoeckler, Mary E.; Vyas, Dolatrai M.; Balasubramanian, Balu N.Bioorganic & Medicinal Chemistry Letters (2003), 13 (8), 1419-1423CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science B.V.)The synthesis and antifungal activity of 5'- and 5'-6'-substituted azasordarin derivs. I [R4 = CH2CCl:CH2, R5 = H, Me, R6 = Me; R4 = CH2CCl:CH2, R5R6 = cyclopentyl; R4 = CH2CCl:CH2, R5 = Me, CHMe2, CH2OH, CF3, spirocyclopentyl, R6 = H; R4 = CH2CBr:CH2, CH2CH:CH2 CH2CMe:CH2, CH2C(CN):CH2, CH2CH:CHCl-cis, CH2CH:CHBr-cis, CH2CH:CCl2, CH2CH:CF2, CH2CH:CMe2, cyclohex-2-enyl, cyclopropylmethyl, iso-Bu, CH2C6H4OMe-4, CH2C6H2Cl-2, 5-chloro-2-thienyl, COCH:CH2, cyclopropylsulfonyl, R5 = Me, R6 = H] are described. Modification of the 5'-position led to the discovery of the spirocyclopentyl analog I (R4 = CH2CCl:CH2, R5 = spirocyclopentyl, R6 = H), which is the first azasordarin to register single-digit MIC values vs. Aspergillus spp. Further investigation identified the 5'-i-Pr deriv. I (R4 = CH2CCl:CH2, R5 = CHMe2, R6 = H), which displays superior pharmacokinetic properties compared to other azasordarins.(e) Kamai, Y.; Kakuta, M.; Shibayama, T.; Fukuoka, T.; Kuwahara, S. Antifungal activities of R-135853, a sordarin derivative, in experimental candidiasis in mice. Antimicrob. Agents Chemother. 2005, 49, 52– 56, DOI: 10.1128/AAC.49.1.52-56.2005[Crossref], [PubMed], [CAS], Google Scholar117ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXjsl2qsQ%253D%253D&md5=89df046e4475e8a761146613dbec231aAntifungal activities of R-135853, a sordarin derivative, in experimental candidiasis in miceKamai, Yasuki; Kakuta, Masayo; Shibayama, Takahiro; Fukuoka, Takashi; Kuwahara, ShogoAntimicrobial Agents and Chemotherapy (2005), 49 (1), 52-56CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)The activities of R-135853, a novel sordarin deriv. that possesses a 1,4-oxazepane ring moiety, were evaluated in vitro and in vivo. R-135853 exhibited potent in vitro activities against Candida albicans (fluconazole-susceptible strains), Candida glabrata, Candida tropicalis, and Cryptococcus neoformans, with MICs at which 90% of isolates were inhibited of 0.03, 1, 0.5, and 0.5 μg/mL, resp. R-135853 also exhibited potent activities against fluconazole-susceptible dose-dependent and fluconazole-resistant strains of C. albicans, with MICs ranging from 0.03 to 0.06 μg/mL. However, R-135853 exhibited weak or no activity against Candida parapsilosis, Candida krusei, and Aspergillus spp. R-135853 exhibited dose-dependent efficacy against exptl. murine hematogenous candidiasis induced by C. albicans when it was administered by both the s.c. and the oral routes and reduced viable cell counts in the kidneys significantly when it was administered at 50 mg/kg of body wt./dose (administration three times a day). In this model, R-135853 also exhibited dose-dependent efficacy by single oral administration. S.c. administration of R-135853 exhibited dose-dependent efficacy against exptl. murine esophageal candidiasis induced by fluconazole-resistant C. albicans, against which fluconazole at 50 mg/kg/dose was ineffective, and reduced viable cell counts in the esophagus significantly when it was administered at 10 and 50 mg/kg/dose. R-135853 eradicated C. albicans from the esophagi of one and four of five mice when it was administered at 10 and 50 mg/kg/dose, resp. These results suggest that R-135853 is promising for the treatment of disseminated or mucosal candidiasis, including fluconazole-refractory infections.
- 118Bueno, A. B.; Agejas, J.; Broughton, H.; Dally, R.; Durham, T. B.; Espinosa, J. F.; Gonzalez, R.; Hahn, P. J.; Marcos, A.; Rodríguez, R.; Sanz, G.; Soriano, J. F.; Timm, D.; Vidal, P.; Yang, H.; McCarthy, J. R. Optimization of hydroxyethylamine transition state isosteres as aspartic protease inhibitors by exploiting conformational preferences. J. Med. Chem. 2017, 60, 9807– 9820, DOI: 10.1021/acs.jmedchem.7b01304[ACS Full Text], [CAS], Google Scholar118https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhslCitb%252FO&md5=7baa111e22231813b64aed6a21181eedOptimization of Hydroxyethylamine Transition State Isosteres as Aspartic Protease Inhibitors by Exploiting Conformational PreferencesBueno, Ana B.; Agejas, Javier; Broughton, Howard; Dally, Robert; Durham, Timothy B.; Espinosa, Juan Felix; Gonzalez, Rosario; Hahn, Patric J.; Marcos, Alicia; Rodriguez, Ramon; Sanz, Gema; Soriano, Jose F.; Timm, David; Vidal, Paloma; Yang, Hsiu-Chiung; McCarthy, James R.Journal of Medicinal Chemistry (2017), 60 (23), 9807-9820CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)NMR Conformational anal. of a hydroxyethylamine peptide isostere developed as an aspartic protease inhibitor shows that it is a flexible architecture. Cyclization to form pyrrolidines, piperidines or morpholines results in a preorganization of the whole system in soln. The resulting conformation is similar to the conformation of the inhibitor in the active site of BACE-1. This entropic gain results in increased affinity for the enzyme when compared with the acyclic system. For morpholines 27 and 29, the combination of steric and electronic factors was exploited to orient substituents toward S1, S1' and S2' pockets both in the soln. and in the bound states. These highly preorganized mols. proved to be the most potent compds. of the series. Addnl., the morpholines, unlike the pyrrolidine and piperidine analogs, were found to be brain penetrant BACE-1 inhibitors.
- 119(a) Eliel, E. I.; Alcudia, F. Acetylcholine analogues. Conformational equilibriums dominated by electrostatic interactions. J. Am. Chem. Soc. 1974, 96, 1939– 1941, DOI: 10.1021/ja00813a051[ACS Full Text.], [CAS], Google Scholar119ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE2cXktVehtro%253D&md5=840e7d2d863d9e59bb7c95aa88fbf1b5Acetylcholine analogs. Conformational equilibriums dominated by electrostatic interactionsEliel, Ernest I.; Alcudia, FelipeJournal of the American Chemical Society (1974), 96 (6), 1939-41CODEN: JACSAT; ISSN:0002-7863.The acid catalyzed equilibration of 2-isopropyl-5-ammonio-, 2-isopropyl-5-dimethylammonio-, 2-isopropyl-5-trimethylammonio- and 2-isopropyl-5-dimethylsulfonio-1,3-dioxane salts favor the axial (cis) isomer by over 2 kcal/mole in all cases. The results are explained on the basis of electrostatic attraction of the positively charged axial substituent and the ring O atoms. The bearing of these findings on the preferred gauche conformation of acetylcholine and the reasons therefore are discussed. H bonding is probably not important in favoring the gauche or axial conformations.(b) Kaloustian, M. K.; Dennis, N.; Mager, S.; Evans, S. A.; Alcudia, F.; Eliel, E. I. Conformational analysis. XXXI. Conformational equilibria of 1,3-dioxanes with polar substituents at C-5. J. Am. Chem. Soc. 1976, 98, 956– 965, DOI: 10.1021/ja00420a015[ACS Full Text], [CAS], Google Scholar119bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE28XhtlCrurc%253D&md5=41c42337be5653ce6a4a0050823da5c2Conformational analysis. XXXI. Conformational equilibria of 1,3-dioxanes with polar substituents at C-5Kaloustian, Moses K.; Dennis, Nicholas; Mager, Sorin; Evans, Slayton A.; Alcudia, Felipe; Eliel, Ernest L.Journal of the American Chemical Society (1976), 98 (4), 956-65CODEN: JACSAT; ISSN:0002-7863.Free energies of isomerization (ΔG°) of isopropyldioxanes (I .dblharw. II; R = CH2OMe, COMe, CO2-, SO2Me, etc.) are reported and compared with previously published data (Eliel, E. L. et al, 1967, 1972, 1973). In a no. of these cases, I are favored at equilibrium even though either steric or dipolar considerations would lead to the opposite prediction. Explanations based on internal solvation, orbital interaction, and charge attractions are considered.
- 120Pasternak, A.; Pan, Y.; Marino, D.; Sanderson, P. E.; Mosley, R.; Rohrer, S. P.; Birzin, E. T.; Huskey, S. W.; Jacks, T.; Schleim, K. D.; Cheng, K.; Schaeffer, J. M.; Patchett, A. A.; Yang, L. Potent, orally bioavailable somatostatin agonists: good absorption achieved by urea backbone cyclization. Bioorg. Bioorg. Med. Chem. Lett. 1999, 9, 491– 496, DOI: 10.1016/S0960-894X(99)00016-5[Crossref], [PubMed], [CAS], Google Scholar120https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXhslSlsr0%253D&md5=31b323b2426b1467b3a92868a1e9b56aPotent, orally bioavailable somatostatin agonists: good absorption achieved by urea backbone cyclizationPasternak, Alexander; Pan, Yanping; Marino, Dominick; Sanderson, Philip E.; Mosley, Ralph; Rohrer, Susan P.; Birzin, Elizabeth T.; Huskey, Su-Er Wu; Jacks, Tom; Schleim, Klaus D.; Cheng, Kang; Schaeffer, James M.; Patchett, Arthur A.; Yang, LihuBioorganic & Medicinal Chemistry Letters (1999), 9 (3), 491-496CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)Backbone cyclization of urea-based somatostatin agonists resulted in novel, orally bioavailable agonists. Binding assays confirmed that the resulting conformationally constrained cyclic ureas retained the potency of their acyclic counterparts. SAR studies subsequently led to highly potent analogs, selective for receptor subtype 2, and having good oral bioavailability.
- 121(a) Li, L.; Okumu, A.; Dellos-Nolan, S.; Li, Z.; Karmahapatra, S.; English, A.; Yalowich, J. C.; Wozniak, D. J.; Mitton-Fry, M. J. Synthesis and anti-staphylococcal activity of novel bacterial topoisomerase inhibitors with a 5-amino-1,3-dioxane linker moiety. Bioorg. Med. Chem. Lett. 2018, 28, 2477– 2480, DOI: 10.1016/j.bmcl.2018.06.003[Crossref], [PubMed], [CAS], Google Scholar.121ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtVOls77M&md5=d510bc73c8fd04d11fb1b7e0f069198bSynthesis and anti-staphylococcal activity of novel bacterial topoisomerase inhibitors with a 5-amino-1,3-dioxane linker moietyLi, Linsen; Okumu, Antony; Dellos-Nolan, Sheri; Li, Zoe; Karmahapatra, Soumendrakrishna; English, Anthony; Yalowich, Jack C.; Wozniak, Daniel J.; Mitton-Fry, Mark J.Bioorganic & Medicinal Chemistry Letters (2018), 28 (14), 2477-2480CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Novel bacterial type II topoisomerase inhibitors (NBTIs) constitute a promising new class of antibacterial agents. The authors report a series of NBTIs with potent anti-staphylococcal activity and diminished hERG inhibition. Dioxane-linked compd. N-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-2-(2-(6-methoxyquinolin-4-yl)ethyl)-trans-1,3-dioxan-5-amine demonstrated MICs ≤1μg/mL against both methicillin-susceptible (MSSA) and -resistant Staphylococcus aureus (MRSA), accompanied by reduced hERG inhibition as compared to cyclohexane- or piperidine-linked analogs.(b) Lu, Y.; Papa, J. L.; Nolan, S.; English, A.; Seffernick, J. T.; Shkolnikov, N.; Powell, J.; Lindert, S.; Wozniak, D. J.; Yalowich, J.; Mitton-Fry, M. J. Dioxane-linked amide derivatives as novel bacterial topoisomerase inhibitors against Gram-positive Staphylococcus aureus. ACS Med. Chem. Lett. 2020, 11, 2446– 2454, DOI: 10.1021/acsmedchemlett.0c00428[ACS Full Text], [CAS], Google Scholar121bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXitVynsL7L&md5=1bfec4b3fef8315a4d5b41707b204191Dioxane-Linked Amide Derivatives as Novel Bacterial Topoisomerase Inhibitors against Gram-Positive Staphylococcus aureusLu, Yanran; Papa, Jonathan L.; Nolan, Sheri; English, Anthony; Seffernick, Justin T.; Shkolnikov, Nicholas; Powell, Josh; Lindert, Steffen; Wozniak, Daniel J.; Yalowich, Jack; Mitton-Fry, Mark J.ACS Medicinal Chemistry Letters (2020), 11 (12), 2446-2454CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)In recent years, novel bacterial topoisomerase inhibitors (NBTIs) have been developed as future antibacterials for treating multidrug-resistant bacterial infections. A series of dioxane-linked NBTIs with an amide moiety has been synthesized and evaluated. Compd. 3 inhibits DNA gyrase, induces the formation of single strand breaks to bacterial DNA, and achieves potent antibacterial activity against a variety of Gram-pos. pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). Optimization of this series of analogs led to the discovery of a subseries of compds. (22-25) with more potent anti-MRSA activity, dual inhibition of DNA gyrase and topoisomerase IV, and the ability to induce double strand breaks through inhibition of S. aureus DNA gyrase.
- 122Kemp, J. A.; Keebaugh, A.; Edson, J. A.; Chow, D.; Kleinman, M. T.; Chew, Y. C.; McCracken, A. N.; Edinger, A. L.; Kwon, Y. J. Biocompatible chemotherapy for leukemia by acid-cleavable, PEGylated FTY720. Bioconjugate Chem. 2020, 31, 673– 684, DOI: 10.1021/acs.bioconjchem.9b00822[ACS Full Text], [CAS], Google Scholar122https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhs1Smt7o%253D&md5=11a9138ce2f13a57783e75a5275561c4Biocompatible Chemotherapy for Leukemia by Acid-Cleavable, PEGylated FTY720Kemp, Jessica A.; Keebaugh, Andrew; Edson, Julius A.; Chow, David; Kleinman, Michael T.; Chew, Yap Ching; McCracken, Alison N.; Edinger, Aimee L.; Kwon, Young JikBioconjugate Chemistry (2020), 31 (3), 673-684CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)Targeting the inability of cancerous cells to adapt to metabolic stress is a promising alternative to conventional cancer chemotherapy. FTY720 (Gilenya), an FDA-approved drug for the treatment of multiple sclerosis, has recently been shown to inhibit cancer progression through the down-regulation of essential nutrient transport proteins, selectively starving cancer cells to death. However, the clin. use of FTY720 for cancer therapy is prohibited because of its capability of inducing immunosuppression (lymphopenia) and bradycardia when phosphorylated upon administration. A prodrug to specifically prevent phosphorylation during circulation, hence avoiding bradycardia and lymphopenia, was synthesized by capping its hydroxyl groups with polyethylene glycol (PEG) via an acid-cleavable ketal linkage. Improved aq. soly. was also accomplished by PEGylation. The prodrug reduces to fully potent FTY720 upon cellular uptake and induces metabolic stress in cancer cells. Enhanced release of FTY720 at a mildly acidic endosomal pH and the ability to substantially down-regulate cell-surface nutrient transporter proteins in leukemia cells only by an acid-cleaved drug were confirmed. Importantly, the prodrug demonstrated nearly identical efficacy to FTY720 in an animal model of BCR-Abl-driven leukemia without inducing bradycardia or lymphopenia in vivo, highlighting its potential clin. value. The prodrug formulation of FTY720 demonstrates the utility of precisely engineering a drug to avoid undesirable effects by tackling specific mol. mechanisms as well as a financially favorable alternative to new drug development. A multitude of existing cancer therapeutics may be explored for prodrug formulation to avoid specific side effects and preserve or enhance therapeutic efficacy.
- 123Kirby, A. J.; Percy, J. M. Intramolecular proton-transfer catalysis of nucleophilic catalysis of acetal hydrolysis. The hydrolysis of 8-dimethylamino-1-methoxymethoxynaphthalene. J. Chem. Soc., Perkin Trans. 2 1989, 907– 912, DOI: 10.1039/p29890000907[Crossref], [CAS], Google Scholar123https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3cXlsVGkug%253D%253D&md5=a8ed0fab44024fda0df689264221e58cIntramolecular proton-transfer catalysis of nucleophilic catalysis of acetal hydrolysis. The hydrolysis of 8-(dimethylamino)-1-(methoxymethoxy)naphthaleneKirby, Anthony J.; Percy, Jonathan M.Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999) (1989), (7), 907-12CODEN: JCPKBH; ISSN:0300-9580.The cleavage of the conjugate acid of the title aryl Me acetal is catalyzed efficiently by the neighboring Me2NH+ group, and also by added nucleophiles. Hydrolysis and nucleophilic catalysis involve a common mechanism, with obligatory but weak bonding to water or the added nucleophile in the transition state. The key to efficient intramol. proton-transfer catalysis appears to be an intramol. hydrogen bond between the general acid and the leaving-group oxygen which is strong in the product and transition states, but weak or absent in the ground state.
- 124(a) Bi, L.; Zhao, M.; Gu, K.; Wang, C.; Ju, J.; Peng, S. Toward the development of chemoprevention agents (III): Synthesis and anti-inflammatory activities of a new class of 5-glycylamino-2-substituted-phenyl-1,3-dioxacycloalkanes. Bioorg. Med. Chem. 2008, 16, 1764– 1774, DOI: 10.1016/j.bmc.2007.11.017[Crossref], [PubMed], [CAS], Google Scholar.124ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXitVOjurc%253D&md5=ed0bcf0a957f6b39bc3c5ddf41613223Toward the development of chemoprevention agents (III): Synthesis and anti-inflammatory activities of a new class of 5-glycylamino-2-substituted-phenyl-1,3-dioxacycloalkanesBi, Lanrong; Zhao, Ming; Gu, Keli; Wang, Chao; Ju, Jingfang; Peng, ShiqiBioorganic & Medicinal Chemistry (2008), 16 (4), 1764-1774CODEN: BMECEP; ISSN:0968-0896. (Elsevier Ltd.)A new series of 5-glycylamino-2-substituted-phenyl-1,3-dioxacycloalkanes were designed and synthesized. The anti-inflammatory activities of these compds. were tested using the xylene-induced mouse ear edema model. Sixteen of these new compds. exhibited comparable or better anti-inflammatory activities than aspirin suggesting that they can be further developed as potential anti-inflammatory drug leads. In addn., treatment with these anti-inflammatory agents did not prolong tail bleeding time in mice. The structure/activity relationships were also analyzed among these compds. Considering their good efficacy and safety profiles, some 5-glycylamino-2-substituted-phenyl-1,3-dioxacycloalkanes are worthy to be explored further in assessing the possible link between anti-inflammation and cancer prevention.(b) Bi, L.; Zhang, Y.; Zhao, M.; Wang, C.; Chan, P.; Tok, J. B.-H.; Peng, S. Novel synthesis and anti-inflammatory activities of 2,5-disubstituted-dioxacycloalkanes. Bioorg. Med. Chem. 2005, 13, 5640– 5646, DOI: 10.1016/j.bmc.2005.05.032[Crossref], [PubMed], [CAS], Google Scholar124bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXos1ajs7Y%253D&md5=c013d9d82952efc7871fdc65c397d36bNovel synthesis and anti-inflammatory activities of 2,5-disubstituted-dioxacycloalkanesBi, Lanrong; Zhang, Yue; Zhao, Ming; Wang, Chao; Chan, Priscilla; Tok, Jeffrey B.-H.; Peng, ShiqiBioorganic & Medicinal Chemistry (2005), 13 (19), 5640-5646CODEN: BMECEP; ISSN:0968-0896. (Elsevier Ltd.)A novel stereospecific synthetic route to obtain a series of 2,5-disubstituted-dioxacycloalkanes is reported. Using an in vivo inhibition assay by monitoring xylene-induced ear edema in mice, the structure-activity relationship of the dioxacycloalkane compds. was studied, and compds. possessing high anti-inflammatory activity were identified.
- 125(a) Dovgan, I.; Kolodych, S.; Koniev, O.; Wagner, A. 2-(Maleimidomethyl)-1,3-dioxanes (MD): a serum-stable self-hydrolysable hydrophilic alternative to classical maleimide conjugation. Sci. Rep. 2016, 6, 30835, DOI: 10.1038/srep30835[Crossref], [PubMed], [CAS], Google Scholar.125ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtlCisbbO&md5=6be2bf9187983ec52f6650841df724e32-(Maleimidomethyl)-1,3-Dioxanes (MD): a Serum-Stable Self-hydrolysable Hydrophilic Alternative to Classical Maleimide ConjugationDovgan, Igor; Kolodych, Sergii; Koniev, Oleksandr; Wagner, AlainScientific Reports (2016), 6 (), 30835CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)The vast majority of antibody-drug conjugates (ADC) are prepd. through amine-to-thiol conjugation. To date, N-Succinimidyl-4-(maleimidomethyl) cyclohexanecarboxylate (SMCC) has been one of the most frequently applied reagents for the prepn. of ADC and other functional conjugates. However, SMCC-based conjugates suffer from limited stability in blood circulation and from a hydrophobic character of the linker, which may give rise to major pharmacokinetic implications. To address this issue, we have developed a heterobifunctional analog of a SMCC reagent, i.e., sodium 4-((maleimidomethyl-1,3-dioxane-5-carbonyl)oxy)-2,3,5,6- tetrafluorobenzenesulfonate (MDTF) for amine-to-thiol conjugation. By replacing the cyclohexyl ring in the SMCC structure with the 1,3-dioxane, we increased the hydrophilicity of the linker. A FRET probe based on MD linker was prepd. and showed superior stability compared to the MCC linker in human plasma, as well as in a variety of aq. buffers. A detailed investigation demonstrated an accelerated succinimide ring opening for MD linker, resulting in stabilized conjugates. Finally, the MDTF reagent was applied for the prepn. of serum stable antibody-dye conjugate.(b) Tobaldi, E.; Dovgan, I.; Mosser, M.; Becht, J.-M.; Wagner, A. Structural investigation of cyclo-dioxo maleimide cross-linkers for acid and serum stability. Org. Biomol. Chem. 2017, 15, 9305– 9310, DOI: 10.1039/C7OB01757J[Crossref], [PubMed], [CAS], Google Scholar125bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhslCnu7rF&md5=5969f8aea1e535eb15feb2951e22ad4aStructural investigation of cyclo-dioxo maleimide cross-linkers for acid and serum stabilityTobaldi, Elisabetta; Dovgan, Igor; Mosser, Michel; Becht, Jean-Michel; Wagner, AlainOrganic & Biomolecular Chemistry (2017), 15 (44), 9305-9310CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)The biochem. characteristics of hetero-bifunctional cross-linkers used in bioconjugates are of essential importance to the desired features of the final adduct (i.e. antibody-drug conjugates). These include stability in biol. media, chem. and biol. reactivities, cleavability under defined conditions, and soly. In our previous work, we introduced a new amino-to-thiol linker, maleimidomethyldioxane (MD), as an alternative to classical maleimide conjugation, with increased hydrophilicity and serum stability due to succinimidyl ring-opening. In this work, we investigated the generality of linkers contg. a dioxo-ring with regard to their ability to self-hydrolyze and their surprising stability at a low pH. We synthesized 3 FRET probes which allowed us to address the stability of the dioxo-ring and to study the maleimide ring-opening and the thiol-exchange processes by means of detecting and measuring the generation of fluorescence. It was found that the ring expansion (from a 5- to a 6-membered ring) improved the stability of the probes in aq. media, and the increase of the chain length between the dioxo-ring and the succinimide ring (from methylene to ethylene) decreased the rate of succinimidyl ring-opening.
- 126Maertens, J. A. History of the development of azole derivatives. Clin. Microbiol. Infect. 2004, 10, 1– 10, DOI: 10.1111/j.1470-9465.2004.00841.x[Crossref], [PubMed], [CAS], Google Scholar126https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXjtFymu7Y%253D&md5=d57e2d90d93844d58562d357652fd1d7History of the development of azole derivativesMaertens, J. A.Clinical Microbiology and Infection (2004), 10 (Suppl. 1), 1-10CODEN: CMINFM; ISSN:1198-743X. (Blackwell Publishing Ltd.)A review. Until the 1940s, relatively few agents were available for the treatment of systemic fungal infections. The development of the polyene antifungals represented a major advance in medical mycol. Although amphotericin B quickly became the mainstay of therapy for serious infections, its use was assocd. with infusion-related side-effects and dose-limiting nephrotoxicity. The continued search for new and, less toxic antifungals led to the discovery of the azoles several decades later. Ketoconazole, the first available compd. for the oral treatment of systemic fungal infections, was released in the early 1980s. For almost a decade, ketoconazole was regarded as the drug of choice in nonlife-threatening endemic mycoses. The introduction of the first-generation triazoles represented a second major advance in the treatment of fungal infections. Both fluconazole and itraconazole displayed a broader spectrum of antifungal activity than the imidazoles and had a markedly improved safety profile compared with amphotericin B and ketoconazole. Despite widespread use, however, these agents became subject to a no. of clin. important limitations related to their suboptimal spectrum of activity, the development of resistance, the induction of hazardous drug-drug interactions, their less than optimal pharmacokinetic profile (itraconazole capsules), and toxicity. To overcome these limitations, several analogs have been developed. These so-called 'second-generation' triazoles, including voriconazole, posaconazole and ravuconazole, have greater potency and possess increased activity against resistant and emerging pathogens, in particular against Aspergillus spp. If the toxicity profile of these agents is comparable to or better than that of the first-generation triazoles and drug interactions remain manageable, then these compds. represent a true expansion of our antifungal arsenal.
- 127Heeres, J.; Backx, L. J. J.; Mostmans, J. H.; Van Cutsem, J. Antimycotic imidazoles. Part 4. Synthesis and antifungal activity of ketoconazole, a new potent orally active broad-spectrum antifungal agent. J. Med. Chem. 1979, 22, 1003– 1005, DOI: 10.1021/jm00194a023[ACS Full Text], [CAS], Google Scholar127https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE1MXks1ymsrc%253D&md5=2e33090d948cc691b14e01a8d371093dAntimycotic imidazoles. Part 4. Synthesis and antifungal activity of ketoconazole, a new potent orally active broad-spectrum antifungal agentHeeres, J.; Backx, L. J. J.; Mostmans, J. H.; Van Cutsem, J.Journal of Medicinal Chemistry (1979), 22 (8), 1003-5CODEN: JMCMAR; ISSN:0022-2623.Ketoconazole (I) [65277-42-1], prepd. from 2,4-dichloroacetophenone [2234-16-4], had complete or marked growth inhibitory activity against a no. of fungi and bacteria. The antifungal effect of I in vitro depended on the test medium. In vivo, I given orally, was effective against exptl. cutaneous candidosis in guinea pigs and vaginal candidosis in rats.
- 128(a) Vanden Bossche, H.; Heeres, J.; Backx, L. J. J.; Marichal, P.; Willemsens, G. Discovery, chemistry, mode of action, and selectivity of itraconazole. In Cutaneus Antifungal Agents; Rippon, J. W., Fromtling, R. A., Eds.; Marcel Decker Inc.: New York, 1993; pp 263– 283.(b) Martin, M. V. The use of fluconazole and itraconazole in the treatment of Candida albicans infections: a review. J. Antimicrob. Chemother. 1999, 44, 429– 437, DOI: 10.1093/jac/44.4.429[Crossref], [PubMed], [CAS], Google Scholar128bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXntV2lurs%253D&md5=e3f831937fab31bb98569375c7f4f1f2The use of fluconazole and itraconazole in the treatment of Candida albicans infections: a reviewMartin, Michael V.Journal of Antimicrobial Chemotherapy (1999), 44 (4), 429-437CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)A review with 93 refs. Candida albicans is responsible for most fungal infections in humans. Fluconazole is well established as a first-line management option for the treatment and prophylaxis of localized and systemic C. albicans infections. Fluconazole exhibits predictable pharmacokinetics and is effective, well tolerated and suitable for use in most patients with C. albicans infections, including children, the elderly and those with impaired immunity. Prophylactic administration of fluconazole can help to prevent fungal infections in patients receiving cytotoxic cancer therapy. The increasing use of fluconazole for the long-term prophylaxis and treatment of recurrent oral candidosis in AIDS patients has led to the emergence of C. albicans infections that are not responsive to conventional doses. Second-line therapy with a wider spectrum anti-fungal, such as itraconazole, should be sought if treatment with fluconazole fails. A soln. formulation of itraconazole has recently been introduced to overcome the poor and variable absorption of its original capsule formulation. Efficacy and tolerability studies in HIV-pos. or immunocompromised patients with C. albicans infections have shown that, although itraconazole soln. is as effective as fluconazole, it is less well tolerated as first-line therapy. Itraconazole soln. can be effective in AIDS patients with C. albicans infections that are non-responsive to fluconazole. No efficacy or tolerability data are available on the use of itraconazole soln. in children or the elderly.
- 129Fukami, T.; Iida, A.; Konishi, K.; Nakajima, M. Human arylacetamide deacetylase hydrolyzes ketoconazole to trigger hepatocellular toxicity. Biochem. Pharmacol. 2016, 116, 153– 161, DOI: 10.1016/j.bcp.2016.07.007[Crossref], [PubMed], [CAS], Google Scholar129https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtFyiu7bO&md5=b23ad627ac6478c8ba2ec987388bdc92Human arylacetamide deacetylase hydrolyzes ketoconazole to trigger hepatocellular toxicityFukami, Tatsuki; Iida, Azumi; Konishi, Keigo; Nakajima, MikiBiochemical Pharmacology (Amsterdam, Netherlands) (2016), 116 (), 153-161CODEN: BCPCA6; ISSN:0006-2952. (Elsevier B.V.)Ketoconazole (KC), an antifungal agent, rarely causes severe liver injury when orally administered. It has been reported that KC is mainly hydrolyzed to N-deacetyl ketoconazole (DAK), followed by the N-hydroxylation of DAK by flavin-contg. monooxygenase (FMO). Although the metab. of KC has been considered to be assocd. with hepatotoxicity, the responsible enzyme(s) remain unknown. The purpose of this study was to identify the responsible enzyme(s) for KC hydrolysis in humans and to clarify their relevance to KC-induced toxicity. Kinetic anal. and inhibition studies using human liver microsomes (HLM) and recombinant enzymes revealed that human arylacetamide deacetylase (AADAC) is responsible for KC hydrolysis to form DAK, and confirmed that FMO3 is the enzyme responsible for DAK N-hydroxylation. In HLM, the clearance of KC hydrolysis occurred to the same extent as DAK N-hydroxylation, which indicates that both processes are not rate-limiting pathways. Cytotoxicity of KC and DAK was evaluated using HepaRG cells and human primary hepatocytes. Treatment of HepaRG cells with DAK for 24 h showed cytotoxicity in a dose-dependent manner, whereas treatment with KC did not show due to the low expression of AADAC. Overexpression of AADAC in HepaRG cells with an adenovirus expression system elicited the cytotoxicity of KC. Cytotoxicity of KC in human primary hepatocytes was attenuated by diisopropylfluorophosphate, an AADAC inhibitor. In conclusion, the present study demonstrated that human AADAC hydrolyzes KC to trigger hepatocellular toxicity.
- 130(a) Niwa, T.; Imagawa, Y.; Yamazaki, H. Drug interactions between nine antifungal agents and drugs metabolized by human cytochromes P450. Curr. Drug Metab. 2015, 15, 651– 679, DOI: 10.2174/1389200215666141125121511 .(b) Khojasteh, S. C.; Prabhu, S.; Kenny, J. R.; Halladay, J. S.; Lu, A. Y. H. Chemical inhibitors of cytochrome P450 isoforms in human liver microsomes: a re-evaluation of P450 isoform selectivity. Eur. J. Drug Metab. Pharmacokinet. 2011, 36, 1– 16, DOI: 10.1007/s13318-011-0024-2[Crossref], [PubMed], [CAS], Google Scholar130bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXisleqsbk%253D&md5=b33b9fd9e9f59f88ca4e5cb242ac0fb4Chemical inhibitors of cytochrome P450 isoforms in human liver microsomes: a re-evaluation of P450 isoform selectivityKhojasteh, Siamak Cyrus; Prabhu, Saileta; Kenny, Jane R.; Halladay, Jason S.; Lu, Anthony Y. H.European Journal of Drug Metabolism and Pharmacokinetics (2011), 36 (1), 1-16CODEN: EJDPD2; ISSN:0378-7966. (Springer France)A review. The majority of marketed small-mol. drugs undergo metab. by hepatic Cytochrome P 450 (CYP) enzymes (Rendic 2002). Since these enzymes metabolize a structurally diverse no. of drugs, metab.-based drug-drug interactions (DDIs) can potentially occur when multiple drugs are coadministered to patients. Thus, a careful in vitro assessment of the contribution of various CYP isoforms to the total metab. is important for predicting whether such DDIs might take place. One method of CYP phenotyping involves the use of potent and selective chem. inhibitors in human liver microsomal incubations in the presence of a test compd. The selectivity of such inhibitors plays a crit. role in deciphering the involvement of specific CYP isoforms. Here, we review published data on the potency and selectivity of chem. inhibitors of the major human hepatic CYP isoforms. The most selective inhibitors available are furafylline (in co-incubation and pre-incubation conditions) for CYP1A2, 2-phenyl-2-(1-piperidinyl)propane (PPP) for CYP2B6, montelukast for CYP2C8, sulfaphenazole for CYP2C9, (-)-N-3-benzyl-phenobarbital for CYP2C19 and quinidine for CYP2D6. As for CYP2A6, tranylcypromine is the most widely used inhibitor, but on the basis of initial studies, either (3-(pyridin-3-yl)-1H-pyrazol-5-yl)methanamine (PPM) and 3-(2-methyl-1H-imidazol-1-yl)pyridine (MIP) can replace tranylcypromine as the most selective CYP2A6 inhibitor. For CYP3A4, ketoconazole is widely used in phenotyping studies, although azamulin is a far more selective CYP3A inhibitor. Most of the phenotyping studies do not include CYP2E1, mostly because of the limited no. of new drug candidates that are metabolized by this enzyme. Among the inhibitors for this enzyme, 4-methylpyrazole appears to be selective.
- 131(a) Van Tyle, J. H. Ketoconazole; Mechanism of action, spectrum of activity, pharmacokinetics, drug interactions, adverse reactions and therapeutic use. Pharmacotherapy 1984, 4, 343– 373, DOI: 10.1002/j.1875-9114.1984.tb03398.x[Crossref], [PubMed], [CAS], Google Scholar.131ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL2M%252FovVWnsg%253D%253D&md5=b51d809c5dc7d7f01c7a268fbc776c22Ketoconazole. Mechanism of action, spectrum of activity, pharmacokinetics, drug interactions, adverse reactions and therapeutic useVan Tyle J HPharmacotherapy (1984), 4 (6), 343-73 ISSN:0277-0008.Ketoconazole is a well-tolerated oral antifungal agent with a broad spectrum of activity in vitro, but in vitro testing has not yet been correlated to in vivo results. In addition, many variables that can alter in vitro test results have been identified. The drug shows effectiveness in the treatment of paracoccidioidomycosis, chronic mucocutaneous candidiasis, oral thrush, coccidioidomycosis and histoplasmosis. It was recently approved for use in blastomycosis. It is not yet approved for use in dermatophyte infections, but a large body of literature exists supporting this application. Ketoconazole has several reported drug interactions, including lower bioavailability with cimetidine, accumulation of cyclosporin during concurrent therapy and a possible disulfiram-like reaction with alcohol. It is highly protein bound to albumin and is extensively metabolized. Dosage adjustment is not required in renal failure. The main side effects are gastrointestinal and occur in 5-10% of the patients. Rare side effects include gynecomastia and hepatotoxicity. The latter is reported to occur in 1 of 12,000 patients. Ketoconazole impairs testosterone synthesis, and therefore it is recommended that administration more than once daily be avoided in men. The usual dosage is 200-400 mg administered once daily. Few comparative or controlled studies have been published thus far. How it compares to amphotericin B is not known. The optimum dosage and the optimum duration of therapy are not established.(b) Rodriguez, R. J.; Acosta, D., Jr. Metabolism of ketoconazole and deacetylated ketoconazole by rat hepatic microsomes and flavin-containing monooxygenases. Drug Metab. Dispos. 1997, 25, 772– 777[PubMed], [CAS], Google Scholar131bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXktFGnsr0%253D&md5=24a271ccf1450134bd59216602676544Metabolism of ketoconazole and deacetylated ketoconazole by rat hepatic microsomes and flavin-containing monooxygenasesRodriguez, Rosita J.; Acosta, Daniel, Jr.Drug Metabolism and Disposition (1997), 25 (6), 772-777CODEN: DMDSAI; ISSN:0090-9556. (Williams & Wilkins)Ketoconazole (KT) has been reported to cause hepatotoxicity, which is probably not mediated through an immunoallergic mechanism. Although KT is extensively metabolized by hepatic microsomal enzymes, the nature, route of formation, and toxicity suspected metabolites are largely unknown. Recent reports indicate that N-deacetyl ketoconazole (DAK) is a major initial metabolite in mice, which, like lipophilic-4-alkylpiperazines, is susceptible to successive oxidative attacks on the N-1 position producing ring-opened dialdehydes. The rate of formation of DAK from hepatic rat microsomal incubations of KT was detd. by HPLC. The rate of disappearance for KT was almost equal to the rate of DAK formation: 5.96 and 5.88 μM/h, resp. Also, the potential bioactivation of DAK was evaluation by measuring substrate activity of DAK with purified pig liver flavin-contg. monooxygenase (FMO) and rat liver microsomes. Activity was measured by following DAK-dependent oxygen uptake polarog. at 37°C in pyrophosphate buffer (pH 8.8) contg. the glucose-6-phosphate NADPH-generating system. The KM's of DAK were 34.6 and 77.4 μM for the purified FMO and rat microsomal FMO, resp. Lastly, DAK was found to be metabolized by an NADPH-dependent rat liver microsomal monooxygenases at pH 8.8 to two metabolites as detd. by HPLC. Heat inactivation of rat liver microsomal FMO abolished the formation of these metabolites from DAK. SKF-525A and anti-rat NADPH cytochrome P 450 reductase did not inhibit this reaction. These results suggest that deacetylation of KT yields a major product, DAK, for further metab. by microsomal monooxygenases that seem to be FMO-related.
- 132(a) Poirier, J. M.; Lebot, M.; Descamps, P.; Levy, M.; Cheymol, G. Determination of itraconazole and its active metabolite in plasma by column liquid chromatography. Ther. Drug Monit. 1994, 16, 596– 601, DOI: 10.1097/00007691-199412000-00011[Crossref], [PubMed], [CAS], Google Scholar.132ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXivVKjtr0%253D&md5=e12bb84ab00e418e53d338e921494904Determination of itraconazole and its active metabolite in plasma by column liquid chromatographyPoirier, Jean-Marie; Lebot, Martine; Descamps, Philippe; Levy, Monique; Cheymol, GeorgesTherapeutic Drug Monitoring (1994), 16 (6), 596-601CODEN: TDMODV; ISSN:0163-4356.Oral itraconazole is effective against a wide range of fungal pathogens that includes Aspergillus species, and its use in leukemic and AIDS patients is currently on the increase. Itraconazole undergoes extensive metab. and the main isolated metabolite, hydroxyitraconazole, is found in plasma at concns. 2-3-fold higher than parent drug and presents in vitro the same antifungal activity. At present, despite the contribution of this metabolite to the overall activity of the drug, no well-documented assay was reported in the literature for the simultaneous detn. of itraconazole and hydroxyitraconazole in plasma. Due to the wide variety of coadministered drugs to patients receiving itraconazole, the purpose of the developed method was to obtain a specific assay sensitive enough for itraconazole therapeutic monitoring. Therefore, a 3-step liq.-liq. extn. procedure followed by reversed-phase HPLC and spectrofluorimetric detection was performed. This assay allowed detn. of 20 ng/mL of both itraconazole and its active metabolite with an acceptable precision using a 0.5-mL plasma sample; no analytic interference was encountered from 45 coadministered drugs tested.(b) Peng, C. C.; Shi, W.; Lutz, J. D.; Kunze, K. L.; Liu, J. O.; Nelson, W. L.; Isoherranen, N. Stereospecific metabolism of itraconazole by CYP3A4: dioxolane ring scission of azole antifungals. Drug Metab. Dispos. 2012, 40, 426– 435, DOI: 10.1124/dmd.111.042739[Crossref], [PubMed], [CAS], Google Scholar132bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xjs1WqtLc%253D&md5=366d102f96b6d538a73cfab0eece23ceStereospecific metabolism of itraconazole by CYP3A4: dioxolane ring scission of azole antifungalsPeng, Chi-Chi; Shi, Wei; Lutz, Justin D.; Kunze, Kent L.; Liu, Jun O.; Nelson, Wendel L.; Isoherranen, NinaDrug Metabolism & Disposition (2012), 40 (3), 426-435CODEN: DMDSAI; ISSN:1521-009X. (American Society for Pharmacology and Experimental Therapeutics)Itraconazole (ITZ) is a mixt. of four cis-stereoisomers that inhibit CYP3A4 potently and coordinate CYP3A4 heme via the triazole nitrogen. However, (2R,4S,2'R)-ITZ and (2R,4S,2'S)-ITZ also undergo stereoselective sequential metab. by CYP3A4 at a site distant from the triazole ring to 3'-OH-ITZ, keto-ITZ, and N-desalkyl-ITZ. This stereoselective metab. demonstrates specific interactions of ITZ within the CYP3A4 active site. To further investigate this process, the binding and metab. of the four trans-ITZ stereoisomers by CYP3A4 were characterized. All four trans-ITZ stereoisomers were tight binding inhibitors of CYP3A4-mediated midazolam hydroxylation (IC50 16-26 nM), and each gave a type II spectrum upon binding to CYP3A4. However, instead of formation of 3'-OH-ITZ, they were oxidized at the dioxolane ring, leading to ring scission and formation of two new metabolites of ITZ. These two metabolites were also formed from the four cis-ITZ stereoisomers, although not as efficiently. The catalytic rates of dioxolane ring scission were similar to the dissocn. rates of ITZ stereoisomers from CYP3A4, suggesting that the heme iron is reduced while the triazole moiety coordinates to it and no dissocn. of ITZ is necessary before catalysis. The triazole contg. metabolite [1-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone] also inhibited CYP3A4 (IC50 >15 μM) and showed type II binding with CYP3A4. The dioxolane ring scission appears to be clin. relevant because this metabolite was detected in urine samples from subjects that had been administered the mixt. of cis-ITZ isomers. These data suggest that the dioxolane ring scission is a metabolic pathway for drugs that contain this moiety.
- 133(a) Sawyer, P. R.; Brogden, R. N.; Pinder, R. M.; Speight, T. M.; Avery, G. S. Miconazole: review of its antifungal activity and therapeutic efficacy. Drugs 1975, 9, 406– 423, DOI: 10.2165/00003495-197509060-00002[Crossref], [PubMed], [CAS], Google Scholar.133ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE2MXlslahtLk%253D&md5=450bfc9d39bf0f4f1b6f9bc80197a22bMiconazole. Review of its antifungal activity and therapeutic efficacySawyer, Phyllis R.; Brogden, R. N.; Pinder, R. M.; Speight, T. M.; Avery, G. S.Drugs (1975), 9 (6), 406-23CODEN: DRUGAY; ISSN:0012-6667.A review of the pharmacol. of miconazole nitrate (I) [22832-87-7]; 30 refs.(b) Fothergill, A. W. Miconazole: a historical perspective. Expert Rev. Anti-Infect. Ther. 2006, 4, 171– 175, DOI: 10.1586/14787210.4.2.171[Crossref], [PubMed], [CAS], Google Scholar133bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XktVSjsLc%253D&md5=9d7d813082801dc577c65ede0ff6b1f4Miconazole: a historical perspectiveFothergill, Annette W.Expert Review of Anti-Infective Therapy (2006), 4 (2), 171-175CODEN: ERATCK; ISSN:1478-7210. (Future Drugs Ltd.)A review. Miconazole is an imidazole that has been successfully used for over 30 years for the treatment of superficial and cutaneous disease. This agent is distinguished from other azoles by possessing two mechanisms of action. The first mechanism is shared with other azoles and involves the inhibition of ergosterol synthesis. Another mechanism involves inhibition of peroxidases, which results in the accumulation of peroxide within the cell resulting in cell death. Susceptibility patterns for miconazole demonstrate that yeast fungi remain largely susceptible even in light of repeated exposures. Despite the release of newer azoles and other classes of antifungals, miconazole remains a highly prescribed treatment for vaginal candidiasis.
- 134Godefroi, E. F.; Heeres, J.; Van Cutsem, J.; Janssen, P. A. J. The preparation and antimycotic properties of derivatives of 1-phenethylimidazole. J. Med. Chem. 1969, 12, 784– 791, DOI: 10.1021/jm00305a014[ACS Full Text], [CAS], Google Scholar134https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF1MXltFartLw%253D&md5=2abc3cb646059f4af1147cff78a19630Preparation and antimycotic properties of derivatives of 1-phenethylimidazoleGodefroi, Erik F.; Heeres, Jan; Van Cutsem, Jan; Janssen, Paul A. J.Journal of Medicinal Chemistry (1969), 12 (5), 784-91CODEN: JMCMAR; ISSN:0022-2623.The synthesis of a large no. of β-substituted-1-phenethylimidazoles is described. Many appropriately N-substituted-1-(β-aminophenethyl)imidazoles and cyclic ketals derived from 2-(1-imidazolyl)acetophenones were quite active against dermatophytes. However, 1-(β-benzyloxyphenethyl)-imidazoles displayed potent, broad-spectrum activity, not only against dermatophytes but also against yeast cells (Candida albicans) and gram-pos. bacteria.
- 135Heeres, J.; Van Cutsem, J. Antimycotic imidazoles. 5. Synthesis and antimycotic properties of 1-[[2-aryl-4-(arylalkyl)-1,3-dioxolan-2-yl]methyl]-1H-imidazoles. J. Med. Chem. 1981, 24, 1360– 1364, DOI: 10.1021/jm00143a019[ACS Full Text], [CAS], Google Scholar135https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL3MXls1Wktb4%253D&md5=ff28d3f4257300c6f76ced0a6069db9eAntimycotic imidazoles. 5. Synthesis and antimycotic properties of 1-[[2-aryl-4-(arylalkyl)-1,3-dioxolan-2-yl]methyl]-1H-imidazolesHeeres, J.; Van Cutsem, J.Journal of Medicinal Chemistry (1981), 24 (11), 1360-4CODEN: JMCMAR; ISSN:0022-2623.Forty title compds. I (R and R1 = H, Cl, Br, or Me; R2 and R3 = H, Br, Cl, OMe, Ph, etc.; n = 0-2) were synthesized and tested in vivo and in vitro for antifungal and antibacterial activities. Most of the compds. had high in vitro activity against dermatophytes comparable to miconazole. Some compds. were also active against yeasts, other fungi, and gram-pos. bacteria, but they had no activity against gram-neg. bacteria. Alkyl chain length had only minor effects on in vitro activity.
- 136Heeres, J.; Meerpoel, L.; Lewi, P. Conazoles. Molecules 2010, 15, 4129– 4188, DOI: 10.3390/molecules15064129[Crossref], [PubMed], [CAS], Google Scholar136https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXns1KktrY%253D&md5=15947d5d12b9eabe58e87ffa4db15f65ConazolesHeeres, Jan; Meerpoel, Lieven; Lewi, PaulMolecules (2010), 15 (), 4129-4188CODEN: MOLEFW; ISSN:1420-3049. (Molecular Diversity Preservation International)A review. This review provides a historical overview of the analog based drug discovery of miconazole and its congeners, and is focused on marketed azole antifungals bearing the generic suffix "conazole". The antifungal activity of miconazole, one of the first broad-spectrum antimycotic agents has been mainly restricted to topical applications. The attractive in vitro antifungal spectrum was a starting point to design more potent and esp. orally active antifungal agents such as ketoconazole, itraconazole, posaconazole, fluconazole and voriconazole. The chem., in vitro and in vivo antifungal activity, pharmacol., and clin. applications of these marketed conazoles has been described.
- 137Lewis, D. F.; Wiseman, A.; Tarbit, M. H. Molecular modelling of lanosterol 14α-demethylase (CYP51) from Saccharomyces cerevisiae via homology with CYP102, a unique bacterial cytochrome P450 isoform: quantitative structure-activity relationships (QSARs) within two related series of antifungal azole derivatives. J. Enzyme Inhib. 1999, 14, 175– 192, DOI: 10.3109/14756369909030315[Crossref], [PubMed], [CAS], Google Scholar137https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXotFelu7g%253D&md5=02085aee59458f9b17734ec6f4b492cdMolecular modelling of lanosterol 14α-demethylase (CYP51) from Saccharomyces cerevisiae via homology with CYP102, a unique bacterial cytochrome P450 isoform: quantitative structure-activity relationships (QSARs) within two related series of antifungal azole derivativesLewis, David F. V.; Wiseman, Alan; Tarbit, Mike H.Journal of Enzyme Inhibition (1999), 14 (3), 175-192CODEN: ENINEG; ISSN:8755-5093. (Harwood Academic Publishers)The construction of a three-dimensional mol. model of the fungal form of cytochrome P 450 (CYP51) from Saccharomyces cerevisiae, based on homol. with the hemoprotein domain of CYP102 from Bacillus megaterium (a unique bacterial P 450 of known crystal structure) is described. It is found that the endogenous substrate, lanosterol, can readily occupy the putative active site of the CYP51 model such that the known mono-oxygenation reaction, leading to C14-demethylation of lanosterol, is the preferred route of metab. for this particular substrate. Key amino acid contacts within the CYP51 active site appear to orientate lanosterol for oxidative attack at the C14-Me group, and the position of the substrate relative to the hem moiety is consistent with the phenyl-iron complexation studies reported by Tuck et al. Typical azole inhibitors, such as ketoconazole, are able to fit the putative active site of CYP51 by a combination of hem ligation, hydrogen bonding, π-π stacking and hydrophobic interactions within the enzyme's hem environment. The mode of action of azole antifungals, as described by the modeling studies, is supported by quant. structure-activity relationship (QSAR) analyses on two groups of structurally related fungal inhibitors. Moreover, the results of mol. electrostatic isopotential (EIP) energy calcns. are compatible with the proposed mode of binding between azole antifungal agents and the putative active site of CYP51, although membrane interactions may also have a role in the antifungal activity of azole derivs.
- 138(a) Collis, A. J.; Foster, M. L.; Halley, F.; Maslen, C.; McLay, I. M.; Page, K. M.; Redford, E. J.; Souness, J. E.; Wilsher, N. E. RPR203494 a pyrimidine analogue of the p38 inhibitor RPR200765A with an improved in vitro potency. Bioorg. Med. Chem. Lett. 2001, 11, 693– 696, DOI: 10.1016/S0960-894X(01)00034-8[Crossref], [PubMed], [CAS], Google Scholar.138ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXhslOntrg%253D&md5=b4cc561166be1ffbef67596b6d469717RPR203494 a pyrimidine analogue of the p38 inhibitor RPR200765A with an improved in vitro potencyCollis, Alan J.; Foster, Martyn L.; Halley, Frank; Maslen, Christopher; McLay, Iain M.; Page, Kenneth M.; Redford, E. Jane; Souness, John E.; Wilsher, Nicola E.Bioorganic & Medicinal Chemistry Letters (2001), 11 (5), 693-696CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)Following the discovery of RPR200765, a series of pyrimidine analogs have been prepd. as backups. Amongst them, RPR203494 was identified with a better in vitro profile than RPR200765A.(b) McKenna, J. M.; Halley, F.; Souness, J. E.; McLay, I. M.; Pickett, S. D.; Collis, A. J.; Page, K.; Ahmed, I. An algorithm-directed two-component library synthesized via solid-phase methodology yielding potent and orally bioavailable p38 MAP kinase inhibitors. J. Med. Chem. 2002, 45, 2173– 2184, DOI: 10.1021/jm011132l[ACS Full Text], [CAS], Google Scholar138bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XjtFGmtLo%253D&md5=28a03ae9b698df7cd154141127069352An Algorithm-Directed Two-Component Library Synthesized Via Solid-Phase Methodology Yielding Potent and Orally Bioavailable p38 MAP Kinase InhibitorsMcKenna, Jeffrey M.; Halley, Frank; Souness, John E.; McLay, Iain M.; Pickett, Stephen D.; Collis, Alan J.; Page, Kenneth; Ahmed, ImtiazJournal of Medicinal Chemistry (2002), 45 (11), 2173-2184CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Previously we reported the identification of RPR200765A, a potent orally bioavailable pyridine-imidazole inhibitor of p38 mitogen-activated protein (MAP) kinase which suppressed paw swelling and joint pathol. in streptococcal cell wall-induced arthritis. Herein, we report the use of solid-phase combinatorial org. synthesis for the parallel processing of a related pyrimidine-imidazole-based library with two points of structural variability. We report also that the application of a computer algorithm, the Monte Carlo Monomer Selection, maximized both the combinatorial synthetic efficiency and the bioavailability of the final compds. In conjunction with the synthetic protocols, the polymer-supported quench technique was applied to the purifn. of the final compds. Through rapid evaluation of the library using a p38 kinase assay and permeability assays, it was possible to identify a no. of potent and orally bioavailable p38 MAP kinase inhibitors suitable for further biol. investigation.
- 139(a) Abbotto, A.; Bradamante, S.; Pagani, G. A. Diheteroarylmethanes. 5.1 E-Z isomerism of carbanions substituted by 1,3-azoles: 13C and 15N δ-charge/shift relationships as source for mapping charge and ranking the electron-withdrawing power of heterocycles. J. Org. Chem. 1996, 61, 1761– 1769, DOI: 10.1021/jo951884l[ACS Full Text.], [CAS], Google Scholar139ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XhtFersb8%253D&md5=11ce86914febca0b3e37daa0bea80e29Diheteroarylmethanes. 5. E-Z Isomerism of Carbanions Substituted by 1,3-Azoles: 13C and 15N π-Charge/Shift Relationships as Source for Mapping Charge and Ranking the Electron-Withdrawing Power of HeterocyclesAbbotto, Alessandro; Bradamante, Silvia; Pagani, Giorgio A.Journal of Organic Chemistry (1996), 61 (5), 1761-9CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)Previously proposed π-charge/shift relationships have been applied to 13C and 15N shifts of the carbanions of 2-benzylazoles (thiazole, oxazole, and imidazole), their corresponding benzo-fused analogs, and bis(2-azolyl)methanes (azolyl groups as above). In this way it is possible to rank the π electron-withdrawing power of these heterocycles in terms of charge demands cX, a quantity representing the fraction of π neg. charge withdrawn (delocalized) by the ring. The results indicate that cthiaz > coxaz > cimidaz; furthermore, benzo azoles are more efficient than monocyclic systems in delocalizing the neg. charge. The charge demand cX of imidazole is the smallest among the heteroaroms. so far considered, being even smaller than that of the Ph ring. As a consequence, the neg. charge in the anion of 2-benzyl-N-methylimidazole is predominantly transferred from the carbanionic carbon to the Ph group rather than to the imidazolyl residue.The high double bond character of the bond linking the carbanionic and ipso Ph ring carbons leads to room temp. 13C shift anisochrony of the meta and meta' and ortho and ortho' positions of the Ph ring. In all of the other cases, hindered rotation is obsd. at room temp. between the carbanionic carbon and position 2 of the heterocycle. A single set of resonances is presented by the bis(heteroaryl)methyl carbanions. π-Charge/shift relationships allow for the accurate π-charge mapping in these carbanionic systems, and the results point to considerable delocalization of the electron pair(s) of the oxygen and pyrrolic nitrogen atoms at position 1 in oxazole and imidazole toward the pyridic nitrogen at position 3 of the rings (in both the neutrals and the carbanionic species). On the contrary, not only does the sulfur atom in thiazole derivs. not delocalize any neg. charge in the anions but it is barely involved in any π-donation to the pyridic nitrogen atom at position 3 also in the neutrals.(b) Abbotto, A.; Bradamante, S.; Facchetti, A.; Pagani, G. A. Metal chelation aptitudes of bis(o-azaheteroaryl)methanes as tuned by heterocycle charge demands. J. Org. Chem. 2002, 67, 5753– 5772, DOI: 10.1021/jo025696o[ACS Full Text], [CAS], Google Scholar139bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XltFGmtrg%253D&md5=2ff6ed169d69cc8c5e39a5f251397310Metal Chelation Aptitudes of Bis(o-azaheteroaryl)methanes As Tuned by Heterocycle Charge DemandsAbbotto, Alessandro; Bradamante, Silvia; Facchetti, Antonio; Pagani, Giorgio A.Journal of Organic Chemistry (2002), 67 (16), 5753-5772CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)The authors describe the synthesis of a no. of 1,3-azol-2-yl-, 1,3-benzazol-2-yl-, and azinyl-based bis(o-azaheteroaryl)methanes (LH, L- = Het2CH-) and their coordinating properties toward divalent transition metals (Zn, Cu, Co, Ni, Hg, Pd). This extended study includes both sym. and unsym. ligands based on several substituted and/or unsubstituted thiazole, benzothiazole, benzoxazole, benzimidazole, pyridine, and quinoline derivs. Depending on the structure and electron properties of the ligand, a vast set of neutral chelates ML2 were obtained, where the ligand is present in its carbanionic form L-. Addnl., the authors prepd. salt complexes [M(LH)n]Xm, where the ligand is present as a neutral system. Neutral chelates were typically obtained by the reaction of the ligand with metal acetates in alc. soln. Salt complexes were formed by reaction with other metal salts such as chlorides. By exploring the coordinating properties of several bisheteroarylmethane ligands based on heteroaroms. of variable π-electron structure and substitution pattern, the formation of neutral chelates is strictly dependent on the electron-withdrawing capacity (charge demand) of the heteroarom. moiety. The latter primarily dictates the efficiency by which the neg. charge of the anionic ligand L- is stabilized by delocalization in ML2 and, therefore, the stability of the chelate itself. From the large no. and the variable nature of the N ligands used, the authors confirm the general validity of the charge-demand-dependent formation of chelates. This key factor can therefore be used for the efficient design of new π-deficient heteroarom. N ligands in chelates of great potential in many synthetic, catalytic, and technol. fields.
- 140Collis, A.; Halley, F.; McClay, I. Heteroaryl-cyclic acetals. U.S. Patent 7,479,501 B2. January 30th, 2009.
- 141(a) Lovering, F. Escape from flatland 2: complexity and promiscuity. MedChemComm 2013, 4, 515– 519, DOI: 10.1039/c2md20347b[Crossref], [CAS], Google Scholar.141ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjtFShtL0%253D&md5=c03d3b99da22a684cbbbb00fb1633342Escape from Flatland 2: complexity and promiscuityLovering, FrankMedChemComm (2013), 4 (3), 515-519CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)Toxicity plays a major role in attrition in the clinic and promiscuity has been linked to toxicity. A no. of mol. descriptors have been identified that contribute to promiscuity including ionization and logP. In this study we report on the relationship between complexity, as measured by two descriptors [fraction sp3 (Fsp3) where Fsp3 = (no. of sp3 hybridized carbons/total carbon count) and chiral carbon count], and promiscuity as well as Cyp450 inhibition. We find that increasing complexity reduces promiscuity and Cyp450 inhibition. As an understanding of key property descriptors has helped the pharmaceutical industry to address some of the deficiencies of compds. as pertains to bioavailability, awareness of the descriptors that impact promiscuity should allow us to better address toxicity in the clinic.(b) Clemons, P. A.; Bodycombe, N. E.; Carrinski, H. A.; Wilson, J. A.; Shamji, A. F.; Wagner, B. K.; Koehler, A. N.; Schreiber, S. L. Small molecules of different synthetic and natural origins have distinct distributions of structural complexity that correlate with protein binding profiles. Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 18787– 18792, DOI: 10.1073/pnas.1012741107[Crossref], [PubMed], [CAS], Google Scholar.141bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsVCqsb%252FN&md5=198e298ca5391d7dfd91184680e3c2ecSmall molecules of different origins have distinct distributions of structural complexity that correlate with protein-binding profilesClemons, Paul A.; Bodycombe, Nicole E.; Carrinski, Hyman A.; Wilson, J. Anthony; Shamji, Alykhan F.; Wagner, Bridget K.; Koehler, Angela N.; Schreiber, Stuart L.Proceedings of the National Academy of Sciences of the United States of America (2010), 107 (44), 18787-18792, S18787/1-S18787/5CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Using a diverse collection of small mols. generated from a variety of sources, we measured protein-binding activities of each individual compd. against each of 100 diverse (sequence-unrelated) proteins using small-mol. microarrays. We also analyzed structural features, including complexity, of the small mols. We found that compds. from different sources (com., academic, natural) have different protein-binding behaviors and that these behaviors correlate with general trends in stereochem. and shape descriptors for these compd. collections. Increasing the content of sp3-hybridized and stereogenic atoms relative to compds. from com. sources, which comprise the majority of current screening collections, improved binding selectivity and frequency. The results suggest structural features that synthetic chemists can target when synthesizing screening collections for biol. discovery. Because binding proteins selectively can be a key feature of high-value probes and drugs, synthesizing com- pounds having features identified in this study may result in improved performance of screening collections.(c) Meanwell, N. A. Improving drug design: an update on recent applications of efficiency metrics, strategies for replacing problematic elements, and compounds in nontraditional drug space. Chem. Res. Toxicol. 2016, 29, 564– 616, DOI: 10.1021/acs.chemrestox.6b00043[ACS Full Text], [CAS], Google Scholar141chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XktVCrs7Y%253D&md5=aef48399fb698b5f958c1cc11e1d25aaImproving Drug Design: An Update on Recent Applications of Efficiency Metrics, Strategies for Replacing Problematic Elements, and Compounds in Nontraditional Drug SpaceMeanwell, Nicholas A.Chemical Research in Toxicology (2016), 29 (4), 564-616CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)Drug discovery and development is a complex and lengthy enterprise that suffers from high rates of candidate attrition at all stages of the process. The phys., biol., and toxicol. properties of a drug candidate are inextricably linked to its structure, and once a mol. has been synthesized, all subsequent studies along the development path are focused only on assessing and understanding its properties in greater detail. Unfortunately, a full prediction of the biol. properties of a mol. from an anal. of its 2- or 3-dimensional structure is currently beyond our expertise. This backdrop mandates that considerable care be taken at the design stage if a mol. is to be successful in testing a mechanistic concept underlying a disease process and to progress into late stage clin. trials and, ultimately, marketing approval. While there are multiple potential causes of candidate attrition, an introspective anal. of drug design practices over the past decade has focused attention on the perception that contemporary mols. are unnecessarily obese, burdened by high mol. wt. and excessive lipophilicity. This practice is believed to have its roots in the singular pursuit of enhancing potency during lead optimization rather than adopting a more holistic approach to drug design that gives broader consideration to how structural features affect developability properties. In an effort to provide the medicinal chem. community with practical guideposts to enhancing compd. quality in the drug design phase and which can readily be applied, a series of efficiency indexes have been proposed that attempt to define aspects of compd. quality in the context of a series of physicochem. parameters. Of these metrics, lipophilic ligand efficiency (LLE or LipE), which provides an index of the dependence of the potency of a mol. on its intrinsic lipophilicity, has been characterized as the most robust metric that has potential for broad-based application. In this review, after describing the background literature behind the derivation of efficiency metrics and approaches to assessing compd. aesthetics, synopses of some recent practical application in lead optimization campaigns are presented. However, mols. that fall into space beyond that assocd. with traditional drug-like properties are an important part of the current and future landscape, exemplified by the summary of direct acting hepatitis C virus NS3 and NS5A inhibitors that have transformed clin. therapy for this chronic disease. While drug development in nontraditional drug-like space is more challenging and the rules for compd. quality will be different with much still to be understood, careful and disciplined drug design practices will be an essential element of success.
- 142Astles, P. C.; Ashton, M. J.; Bridge, A. W.; Harris, N. V.; Hart, T. W.; Parrott, D. P.; Porter, B.; Riddell, D.; Smith, C.; Williams, R. J. Acyl-CoA:cholesterol O-acyltransferase (ACAT) inhibitors. 2. 2-(1,3-Dioxan-2-yl)-4,5-diphenyl-1H-imidazoles as potent inhibitors of ACAT. J. Med. Chem. 1996, 39, 1423– 1432, DOI: 10.1021/jm9505876[ACS Full Text], [CAS], Google Scholar142https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XhsVyht7w%253D&md5=1ceb0a60072c774e83ee359dd4fb128bAcyl-CoA:cholesterol O-acyltransferase (ACAT) inhibitors. 2. 2-(1,3-Dioxan-2-yl)-4,5-diphenyl-1H-imidazoles as potent inhibitors of ACATAstles, Peter C.; Ashton, Michael J.; Bridge, Andrew W.; Harris, Neil V.; Hart, Terrance W.; Parrott, David P.; Porter, Barry; Riddell, David; Smith, Christopher; Williams, Robert J.Journal of Medicinal Chemistry (1996), 39 (7), 1423-32CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The second in this series of papers concerns the further investigations into the search for a potent bioavailable acyl-CoA:cholesterol O-acyltransferase (ACAT) inhibitor suitable for the treatment of atherosclerosis. The design, synthesis, and structure-activity relation for a series of ACAT inhibitors based on the 2-(1,3-dioxan-2-yl)-4,5-diphenyl-1H-imidazole pharmacophore are described. Compds. bearing simple alkyl or hydroxymethyl substituents at the 5-position of the 1,3-dioxane ring are potent bioavailable inhibitors of the rat hepatic microsomal enzyme in vitro (IC50 < 100 nM) but are only weak inhibitors of the human hepatic enzyme. The authors have found however that 1,3-dioxanes substituted at the 5-cis position with pyrazolylalkyl or aminoalkyl groups are potent inhibitors in vitro of human macrophage ACAT, the potency depending on the nature of the terminal heterocycle and the length of the alkyl chain. An ex vivo bioassay described herein demonstrates that potent inhibitors which contain lipophilic terminal heterocycles do not appear to be systemically available. Less potent but more water sol. compds. are absorbed following oral dosing and achieve plasma levels significantly in excess of their IC50 for ACAT inhibition. These compds. are therefore possible candidates for further investigation as oral antiatherosclerotic agents.
- 143(a) Dostertp, P.; Langlois, M.; Guerret, P.; Ancher, J. F.; Bucher, B.; Mocquet, G. Synthesis and pharmacological properties of analogues of oxapadol, a new analgesic agent. Eur. J. Med. Chem. 1980, 15, 199– 205.(b) Mocquet, G.; Coston, A.; Jalfre, M. Animal pharmacology of oxapadol (MD 720111), a new non-narcotic analgesic. Experientia 1980, 36, 96– 97, DOI: 10.1007/BF02003996[Crossref], [PubMed], [CAS], Google Scholar143bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL3cXht1Wrt7k%253D&md5=358431582af3cdb84e3b3b19df67a58eAnimal pharmacology of oxapadol (MD 720111), a new non-narcotic analgesicMocquet, G.; Coston, A.; Jalfre, M.Experientia (1980), 36 (1), 96-7CODEN: EXPEAM; ISSN:0014-4754.In 4 species oxapadol (I) [56969-22-3] had analgesic activity similar to that of other nonnarcotic ref. analgesics. It also had antipyretic and antiinflammatory effects, and in the analgesic dose range I was devoid of undesirable neurol., gastro-intestinal, and cardiovascular side-effects.
- 144(a) Boureau, F.; Laquais, B.; Vadrot, M.; Willer, J.-C. Human neuropharmacological findings with oxapadol (MD 720111), a new non-narcotic analgesic. Experientia 1980, 36, 97– 98, DOI: 10.1007/BF02003997[Crossref], [PubMed], [CAS], Google Scholar.144ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL3cXhsVSltbc%253D&md5=215c1de2eb3d6793065974601ca069afHuman neuropharmacological findings with oxapadol (MD 720111) a new non-narcotic analgesicBoureau, F.; Laquais, B.; Vadrot, M.; Willer, J. C.Experientia (1980), 36 (1), 97-8CODEN: EXPEAM; ISSN:0014-4754.The effects of MD 720111 (oxapadol)(I) [56969-22-3], a new nonnarcotic analgesic, were tested in man using the elec.-induced nociceptive flexion reflex in the flexor muscles of the lower limb as an index of pain. The drug caused a significant increase in the threshold of the reflex whereas no change was noted with placebo.(b) Ancher, J. F.; Donath, A.; Malnoe, A.; Morizur, J. P.; Strolin Bekedetti, M. Urinary metabolites of oxapadol (MD720111), a new non-narcotic analgesic agent, in the rat, dog and man. Xenobiotica 1981, 11, 519– 530, DOI: 10.3109/00498258109045863[Crossref], [PubMed], [CAS], Google Scholar144bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL38XhtlGhs7g%253D&md5=7e7bdb17edd21622cca675c10ecb0b3aUrinary metabolites of oxapadol (MD720111), a new non-narcotic analgesic agent, in the rat, dog, and manAncher, J. F.; Donath, A.; Malnoe, A.; Morizur, J. P.; Strolin Benedetti, M.Xenobiotica (1981), 11 (8), 519-30CODEN: XENOBH; ISSN:0049-8254.A no. of metabolites of oxapadol (I) [56969-22-3] were isolated from rat, dog, and human urine after a single oral dose of I-14C, and were identified by direct inlet mass spectrometry and chromatog. comparison with ref. compds. I was extensively metabolized and unchanged I was not obsd. in rat or human urine, and only traces seen in dog urine. Nine metabolites were identified in rat and dog urine and 6 in man. The routes of biotransformation were arom. hydroxylation (mainly in the benzimidazole ring), scission of the heterocyclic ring following 2 different paths, and a combination of the two. Regioselectivity was obsd. for arom. hydroxylation as only 3 of the 4 possible monohydroxyoxazepinobenzimidazoles could be detected.
- 145Lenci, E.; Menchi, G.; Saldívar-Gonzalez, F.; Medina-Franco, J. L.; Trabocchi, A. Bicyclic acetals: biological relevance, scaffold analysis, and applications in diversity-oriented synthesis. Org. Biomol. Chem. 2019, 17, 1037– 1052, DOI: 10.1039/C8OB02808G[Crossref], [PubMed], [CAS], Google Scholar145https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisFCktLjE&md5=e7e98d22c9c6c239ec2722ed91166717Bicyclic acetals: biological relevance, scaffold analysis, and applications in diversity-oriented synthesisLenci, Elena; Menchi, Gloria; Saldivar-Gonzalez, Fernanda I.; Medina-Franco, Jose L.; Trabocchi, AndreaOrganic & Biomolecular Chemistry (2019), 17 (5), 1037-1052CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)A review. Natural products (NPs) have been shown to be an extraordinary source of bioactive compds. and three-dimensional complex frameworks that can be useful to produce high-value mol. collections that are able to address "undruggable" and difficult therapeutic targets. Bicyclic acetals are particularly relevant for these purposes, given their key role in several biol. interactions and the structural and stereochem. diversity that comes from the many possible ring combinations. To investigate this topol. diversity, we have systematically characterized in a systematic and detailed manner fused, spiro and bridged bicyclic acetals in a large set of NPs, highlighting the great potential of bicyclic acetals in Diversity-Oriented Synthesis (DOS). Accordingly, a summary of some recent efforts on the development of acetal-contg. small mol. collections through DOS approaches is herein reported.
- 146(a) Nomura, S.; Sakamaki, S.; Hongu, M.; Kawanishi, E.; Koga, Y.; Sakamoto, T.; Yamamoto, Y.; Ueta, K.; Kimata, H.; Nakayama, K.; Tsuda-Tsukimoto, M. Discovery of canagliflozin, a novel c-glucoside with thiophene ring, as sodium-dependent glucose co-transporter 2 inhibitor for the treatment of type 2 diabetes mellitus. J. Med. Chem. 2010, 53, 6355– 6360, DOI: 10.1021/jm100332n[ACS Full Text.], [CAS], Google Scholar146ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXpvVartbk%253D&md5=33c3a6bce5ae74799d051b6f8c06da7eDiscovery of Canagliflozin, a Novel C-Glucoside with Thiophene Ring, as Sodium-Dependent Glucose Co-transporter 2 Inhibitor for the Treatment of Type 2 Diabetes MellitusNomura, Sumihiro; Sakamaki, Shigeki; Hongu, Mitsuya; Kawanishi, Eiji; Koga, Yuichi; Sakamoto, Toshiaki; Yamamoto, Yasuo; Ueta, Kiichiro; Kimata, Hirotaka; Nakayama, Keiko; Tsuda-Tsukimoto, MinoruJournal of Medicinal Chemistry (2010), 53 (17), 6355-6360CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)We discovered that aryl C-glucosides, e.g. I, bearing a heteroarom. ring formed metabolically more stable inhibitors for sodium-dependent glucose co-transporter 2 (SGLT2). Thiophene I (canagliflozin) was a highly potent and selective SGLT2 inhibitor and showed pronounced anti-hyperglycemic effects in high-fat diet fed KK (HF-KK) mice.(b) Lamos, E. M.; Younk, L. M.; Davis, S. N. Canagliflozin, an inhibitor of sodium-glucose cotransporter 2, for the treatment of type 2 diabetes mellitus. Expert Opin. Drug Metab. Toxicol. 2013, 9, 763– 775, DOI: 10.1517/17425255.2013.791282[Crossref], [PubMed], [CAS], Google Scholar146bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXnsl2rtbw%253D&md5=b3fb9cc9c0bb8cd774ea19088c67481cCanagliflozin, an inhibitor of sodium-glucose cotransporter 2, for the treatment of type 2 diabetes mellitusLamos, Elizabeth M.; Younk, Lisa M.; Davis, Stephen N.Expert Opinion on Drug Metabolism & Toxicology (2013), 9 (6), 763-775CODEN: EODMAP; ISSN:1742-5255. (Informa Healthcare)A review. Introduction: is an orally administered sodium glucose cotransporter 2 inhibitor proposed for the treatment of type 2 diabetes. Canagliflozin improves glycemic control in an insulin-independent fashion through inhibition of glucose reuptake in the kidney. Areas covered: This article reviews the available data on the pharmacodynamics, the pharmacokinetics and metab., and the efficacy and safety of canagliflozin. Relevant articles were identified via PubMed using the search term canagliflozin with no date restriction. The authors also discuss the abstrs. from canagliflozin studies presented at large diabetes conferences. Expert opinion: Canagliflozin offers a relatively modest redn. in HbA1c, FPG, and PPG. It has a low incidence of hypoglycemia and a redn. in body wt. Dose adjustment may be recommended in the elderly, those on loop diuretics, and those with an estd. glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 if there are concerns or symptoms of vol.-related side effects. Issues remain with obsd. increases in low-d. lipoprotein cholesterol (LDL-C) and the odds of heart attack and stroke. Canagliflozin offers a novel mechanism of action, a modest glycemic control, and a favorable side-effect profile. It was approved by the US Food and Drug Administration in Apr. 2013 and is undergoing evaluation by the European Medicines Agency.
- 147(a) Meng, W.; Ellsworth, B. A.; Nirschl, A. A.; McCann, P. J.; Patel, M.; Girotra, R. N.; Wu, G.; Sher, P. M.; Morrison, E. P.; Biller, S. A.; Zahler, R. A.; Deshpande, P. P.; Pullockaran, A.; Hagan, D. L.; Morgan, N.; Taylor, J. R.; Obermeier, M. T.; Humphreys, W. G.; Khanna, A.; Discenza, L.; Robertson, J. G.; Wang, A.; Han, S.; Wetterau, J. R.; Janovitz, E. B.; Flint, O. P.; Whaley, J. M.; Washburn, W. N. Discovery of dapagliflozin: a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes. J. Med. Chem. 2008, 51, 1145– 1149, DOI: 10.1021/jm701272q[ACS Full Text.], [CAS], Google Scholar147ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhvFWgtrY%253D&md5=8b31ec17acef23a7507ce6a7d9184eb9Discovery of Dapagliflozin: A Potent, Selective Renal Sodium-Dependent Glucose Cotransporter 2 (SGLT2) Inhibitor for the Treatment of Type 2 DiabetesMeng, Wei; Ellsworth, Bruce A.; Nirschl, Alexandra A.; McCann, Peggy J.; Patel, Manorama; Girotra, Ravindar N.; Wu, Gang; Sher, Philip M.; Morrison, Eamonn P.; Biller, Scott A.; Zahler, Robert; Deshpande, Prashant P.; Pullockaran, Annie; Hagan, Deborah L.; Morgan, Nathan; Taylor, Joseph R.; Obermeier, Mary T.; Humphreys, William G.; Khanna, Ashish; Discenza, Lorell; Robertson, James G.; Wang, Aiying; Han, Songping; Wetterau, John R.; Janovitz, Evan B.; Flint, Oliver P.; Whaley, Jean M.; Washburn, William N.Journal of Medicinal Chemistry (2008), 51 (5), 1145-1149CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The C-aryl glucoside 6 (dapagliflozin) was identified as a potent and selective hSGLT2 inhibitor which reduced blood glucose levels in a dose-dependent manner by as much as 55% in hyperglycemic streptozotocin (STZ) rats. These findings, combined with a favorable ADME profile, have prompted clin. evaluation of dapagliflozin for the treatment of type 2 diabetes.(b) Plosker, G. L. Dapagliflozin: a review of its use in type 2 diabetes mellitus. Drugs 2012, 72, 2289– 2312, DOI: 10.2165/11209910-000000000-00000[Crossref], [PubMed], [CAS], Google Scholar147bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXovVChsg%253D%253D&md5=16042d47f6a1ffabafcde175fb5ca83cDapagliflozin: a review of its use in type 2 diabetes mellitusPlosker, Greg L.Drugs (2012), 72 (17), 2289-2312CODEN: DRUGAY; ISSN:0012-6667. (Adis Data Information BV)A review. Dapagliflozin (Forxiga) is the first in a novel class of glucose-lowering agents known as sodium-glucose co-transporter-2 (SGLT2) inhibitors and is used in the treatment of patients with type 2 diabetes. By inhibiting the transporter protein SGLT2 in the kidneys, dapagliflozin reduces renal glucose reabsorption, leading to urinary glucose excretion and a redn. in blood glucose levels. Unlike oral antidiabetic drugs from several other classes, the efficacy of dapagliflozin is independent of insulin secretion and action. Therefore, when used in combination with other antidiabetic drugs, dapagliflozin provides complementary therapy via its unique mechanism of action. A consistent finding across phase III, randomized, double-blind trials in patients with inadequately controlled type 2 diabetes was that dapagliflozin 5 or 10 mg/day for 24 wk as monotherapy in previously untreated patients, or as add-on combination therapy with metformin, glimepiride, pioglitazone or insulin-based therapy, significantly reduced both glycosylated Hb values (primary endpoint) and fasting plasma glucose levels compared with placebo. Various randomized trials have also shown improvements in postprandial blood glucose with dapagliflozin monotherapy and combination therapy compared with placebo. In addn., dapagliflozin was noninferior to glipizide, in terms of glycemic control after 52 wk, when used as add-on therapy in patients with type 2 diabetes that was inadequately controlled with metformin. In most clin. trials, dapagliflozin was assocd. with redns. in body wt. that were statistically superior to placebo or active comparators. Longer-term extension studies indicate that the efficacy of dapagliflozin is maintained for up to ≈2 years. Dapagliflozin was generally well tolerated in clin. trials of 24 or 52 wk duration and in extension studies of up to ≈2 years. Events suggestive of genital infections and urinary tract infections occurred more frequently among dapagliflozin than placebo recipients. These adverse events are of special interest because they appear to be related to the mechanism of action of dapagliflozin. Dapagliflozin has a low propensity to cause hypoglycemia, esp. when used alone or in combination with metformin, although the incidence of hypoglycemic events reported with dapagliflozin in clin. trials varied depending on the background therapy. Longer-term tolerability/safety data with dapagliflozin are awaited with interest. In conclusion, dapagliflozin, with its unique and complementary mechanism of action, appears to be an important addn. to the therapeutic options for the management of type 2 diabetes, particularly when used as add-on therapy.
- 148Haider, K.; Pathak, A.; Rohilla, A.; Haider, M. R.; Ahmad, K.; Yar, M. S. Synthetic strategy and SAR studies of C-glucoside heteroaryls as SGLT2 inhibitor: a review. Eur. J. Med. Chem. 2019, 184, 111773, DOI: 10.1016/j.ejmech.2019.111773[Crossref], [PubMed], [CAS], Google Scholar148https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvF2rt7bI&md5=4a0504769deefe13bdc3665809c8f7fbSynthetic strategy and SAR studies of C-glucoside heteroaryls as SGLT2 inhibitor: A reviewHaider, Kashif; Pathak, Ankita; Rohilla, Ankit; Haider, Md Rafi; Ahmad, Kamal; Yar, M. ShaharEuropean Journal of Medicinal Chemistry (2019), 184 (), 111773CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)A review with refs. Gliflozins constitute an important class of compds. useful as sodium glucose co-transporter (SGLT2) inhibitors to treat type-II diabetes. They act by blocking sodium-glucose transport protein 2 which is responsible for re-absorption of glucose in the proximal convoluted tubule (PCT) of kidney and thus its inhibition reduces blood glucose level. There are a no. of gliflozins which have been approved by drug regulatory bodies like FDA, EMA and PMDA whereas some others are in pipeline in their late developmental phases. The present review article offers a detailed account of synthetic strategies employed for the synthesis, alternate synthetic routes along with Structure Activity Relationship (SAR) studies of well-established as well as newly developed SGLT2 inhibitors.
- 149(a) Mascitti, V.; Maurer, T. S.; Robinson, R. P.; Bian, J.; Boustany-Kari, C. M.; Brandt, T.; Collman, B. M.; Kalgutkar, A. S.; Klenotic, M. K.; Leininger, M. T.; Lowe, A.; Maguire, R. J.; Masterson, V. M.; Miao, Z.; Mukaiyama, E.; Patel, J. D.; Pettersen, J. C.; Preville, C.; Samas, B.; She, L.; Sobol, Z.; Steppan, C. M.; Stevens, B. D.; Thuma, B. A.; Tugnait, M.; Zeng, D.; Zhu, T. Discovery of a clinical candidate from the structurally unique dioxa-bicyclo[3.2.1]octane class of sodium-dependent glucose cotransporter 2 inhibitors. J. Med. Chem. 2011, 54, 2952– 2960, DOI: 10.1021/jm200049r[ACS Full Text.], [CAS], Google Scholar149ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXktVCntrY%253D&md5=80e156d19d3a6a87a61dca59cc1a0e99Discovery of a Clinical Candidate from the Structurally Unique Dioxa-bicyclo[3.2.1]octane Class of Sodium-Dependent Glucose Cotransporter 2 InhibitorsMascitti, Vincent; Maurer, Tristan S.; Robinson, Ralph P.; Bian, Jianwei; Boustany-Kari, Carine M.; Brandt, Thomas; Collman, Benjamin M.; Kalgutkar, Amit S.; Klenotic, Michelle K.; Leininger, Michael T.; Lowe, Andre; Maguire, Robert J.; Masterson, Victoria M.; Miao, Zhuang; Mukaiyama, Emi; Patel, Jigna D.; Pettersen, John C.; Preville, Cathy; Samas, Brian; She, Li; Sobol, Zhanna; Steppan, Claire M.; Stevens, Benjamin D.; Thuma, Benjamin A.; Tugnait, Meera; Zeng, Dongxiang; Zhu, TongJournal of Medicinal Chemistry (2011), 54 (8), 2952-2960CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)PF-04971729 (I) belongs to a new class of potent and selective sodium-dependent glucose cotransporter 2 inhibitors incorporating a unique dioxa-bicyclo[3.2.1]octane (bridged ketal) ring system. In this paper we present the design, synthesis, preclin. evaluation, and human dose predictions related to I. This compd. demonstrated robust urinary glucose excretion in rats and an excellent preclin. safety profile. It is currently in phase 2 clin. trials and is being evaluated for the treatment of type 2 diabetes.(b) Mascitti, V.; Thuma, B. A.; Smith, A. C.; Robinson, R. P.; Brandt, T.; Kalgutkar, A. S.; Maurer, T. S.; Samas, B.; Sharma, R. On the importance of synthetic organic chemistry in drug discovery: reflections on the discovery of antidiabetic agent ertugliflozin. MedChemComm 2013, 4, 101– 111, DOI: 10.1039/C2MD20163A[Crossref], [CAS], Google Scholar149bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvVymsr%252FF&md5=49ad83c03fb27a8d5c5824e23864b24bOn the importance of synthetic organic chemistry in drug discovery: reflections on the discovery of antidiabetic agent ertugliflozinMascitti, Vincent; Thuma, Benjamin A.; Smith, Aaron C.; Robinson, Ralph P.; Brandt, Thomas; Kalgutkar, Amit S.; Maurer, Tristan S.; Samas, Brian; Sharma, RamanMedChemComm (2013), 4 (1), 101-111CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)A review. The discovery of antidiabetic agent ertugliflozin is described. The compd. belongs to a new class of SGLT2 inhibitors bearing a dioxa-bicyclo[3.2.1]octane motif. This article describes the crit. role that org. synthesis played in both influencing our medicinal chem. strategy and speeding up the progression of our program.
- 150(a) Miao, Z.; Nucci, G.; Amin, N.; Sharma, R.; Mascitti, V.; Tugnait, M.; Vaz, A. D.; Callegari, E.; Kalgutkar, A. S. Pharmacokinetics, metabolism, and excretion of the antidiabetic agent ertugliflozin (PF-04971729) in healthy male subjects. Drug Metab. Dispos. 2013, 41, 445– 456, DOI: 10.1124/dmd.112.049551[Crossref], [PubMed], [CAS], Google Scholar.150ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXitlGisb4%253D&md5=a6ad9f69b2d43b160cb2eec29bdd7c53Pharmacokinetics, metabolism, and excretion of the antidiabetic agent ertugliflozin (PF-04971729) in healthy male subjectsMiao, Zhuang; Nucci, Gianluca; Amin, Neeta; Sharma, Raman; Mascitti, Vincent; Tugnait, Meera; Vaz, Alfin D.; Callegari, Ernesto; Kalgutkar, Amit S.Drug Metabolism & Disposition (2013), 41 (2), 445-456CODEN: DMDSAI; ISSN:1521-009X. (American Society for Pharmacology and Experimental Therapeutics)The disposition of ertugliflozin (PF-04971729), an orally active selective inhibitor of the sodium-dependent glucose cotransporter 2, was studied after a single 25-mg oral dose of [14C]-ertugliflozin to healthy human subjects. Mass balance was achieved with approx. 91% of the administered dose recovered in urine and feces. The total administered radioactivity excreted in feces and urine was 40.9% and 50.2%, resp. The absorption of ertugliflozin in humans was rapid with a Tmax at ∼1.0 h. Of the total radioactivity excreted in feces and urine, unchanged ertugliflozin collectively accounted for ∼35.3% of the dose, suggestive of moderate metabolic elimination in humans. The principal biotransformation pathway involved glucuronidation of the glycoside hydroxyl groups to yield three regioisomeric metabolites, M4a, M4b, and M4c (∼39.3% of the dose in urine), of which M4c was the major regioisomer (∼31.7% of the dose). The structure of M4a and M4c were confirmed to be ertugliflozin -4-O-β- and -3-O-β-glucuronide, resp., via comparison of the HPLC retention time and mass spectra with authentic stds. A minor metabolic fate involved oxidn. by cytochrome P 450 to yield monohydroxylated metabolites M1 and M3 and des-Et ertugliflozin (M2), which accounted for ∼5.2% of the dose in excreta. In plasma, unchanged ertugliflozin and the corresponding 4-O-β- (M4a) and 3-O-β- (M4c) glucuronides were the principal components, which accounted for 49.9, 12.2, and 24.1% of the circulating radioactivity. Overall, these data suggest that ertugliflozin is well absorbed in humans, and eliminated largely via glucuronidation.(b) Raje, S.; Callegari, E.; Sahasrabudhe, V.; Vaz, A.; Shi, H.; Fluhler, E.; Woolf, E. J.; Schildknegt, K.; Matschke, K.; Alvey, C.; Zhou, S.; Papadopoulos, D.; Fountaine, R.; Saur, D.; Terra, S. G.; Stevens, L.; Gaunt, D.; Cutler, D. L. Novel application of the two-period microtracer approach to determine absolute oral bioavailability and fraction absorbed of ertugliflozin. Clin. Transl. Sci. 2018, 11, 405– 411, DOI: 10.1111/cts.12549[Crossref], [PubMed], [CAS], Google Scholar.150bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXht12mt73N&md5=cea34332e94c6042e6affbf32f1718a3Novel Application of the Two-Period Microtracer Approach to Determine Absolute Oral Bioavailability and Fraction Absorbed of ErtugliflozinRaje, Sangeeta; Callegari, Ernesto; Sahasrabudhe, Vaishali; Vaz, Alfin; Shi, Haihong; Fluhler, Eric; Woolf, Eric J.; Schildknegt, Klaas; Matschke, Kyle; Alvey, Christine; Zhou, Susan; Papadopoulos, Dimitris; Fountaine, Robert; Saur, Didier; Terra, Steven G.; Stevens, Lloyd; Gaunt, Daniel; Cutler, David L.Clinical and Translational Science (2018), 11 (4), 405-411CODEN: CTSLCA; ISSN:1752-8062. (Wiley-Blackwell)Ertugliflozin, a sodium glucose cotransporter-2 inhibitor, is approved in the United States for treatment of type 2 diabetes mellitus. A novel two-period study design with 14C microtracer dosing in each period was used to det. abs. oral bioavailability (F) and fraction absorbed (Fa) of ertugliflozin. Eight healthy adult men received 100-μg i.v. 14C-ertugliflozin (400 nCi) dose 1 h after a 15-mg oral unlabeled ertugliflozin dose (period 1), followed by 100μg 14C-ertugliflozin orally along with 15 mg oral unlabeled ertugliflozin (period 2). Unlabeled ertugliflozin plasma concns. were detd. using high-performance liq.-chromatog. tandem mass spectrometry (HPLC-MS/MS). 14C-ertugliflozin plasma concns. were detd. using HPLC-accelerator mass spectrometry (AMS) and 14C urine concns. were detd. using AMS. F ((area under the curve (AUC)p.o./14C-AUCi.v.)*(14C-Dosei.v./Dosep.o.)) and Fa ((14C_Total_Urinep.o./14C_Total_Urinei.v.)* (14C-Dosei.v./14C-Dosep.o.)) were estd. Ests. of F and Fa were 105% and 111%, resp. Oral absorption of ertugliflozin was complete under fasted conditions and F was ∼100%. Ertugliflozin was well tolerated.(c) Fediuk, D. J.; Nucci, G.; Dawra, V. K.; Cutler, D. L.; Amin, N. B.; Terra, S. G.; Boyd, R. A.; Krishna, R.; Sahasrabudhe, V. Overview of the clinical pharmacology of ertugliflozin, a novel sodium-glucose cotransporter 2 (SGLT2) inhibitor. Clin. Pharmacokinet. 2020, 59, 949– 965, DOI: 10.1007/s40262-020-00875-1[Crossref], [PubMed], [CAS], Google Scholar150chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXot1agtrg%253D&md5=49dd2f1558dd9115e94b3eba3e1c9081Overview of the Clinical Pharmacology of Ertugliflozin, a Novel Sodium-Glucose Cotransporter 2 (SGLT2) InhibitorFediuk, Daryl J.; Nucci, Gianluca; Dawra, Vikas Kumar; Cutler, David L.; Amin, Neeta B.; Terra, Steven G.; Boyd, Rebecca A.; Krishna, Rajesh; Sahasrabudhe, VaishaliClinical Pharmacokinetics (2020), 59 (8), 949-965CODEN: CPKNDH; ISSN:0312-5963. (Springer International Publishing AG)Abstr.: Ertugliflozin, a selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), is approved in the US, EU, and other regions for the treatment of adults with type 2 diabetes mellitus (T2DM). This review summarizes the ertugliflozin pharmacokinetic (PK) and pharmacodynamic data obtained during phase I clin. development, which supported the registration and labeling of this drug. The PK of ertugliflozin was similar in healthy subjects and patients with T2DM. Oral absorption was rapid, with time to peak plasma concns. (Tmax) occurring at 1 h (fasted) and 2 h (fed) postdose. The terminal phase half-life ranged from 11 to 18 h and steady-state concns. were achieved by 6 days after initiating once-daily dosing. Ertugliflozin exposure increased in a dose-proportional manner over the tested dose range of 0.5-300 mg. Ertugliflozin is categorized as a Biopharmaceutical Classification System Class I drug with an abs. bioavailability of ∼ 100% under fasted conditions. Administration of the ertugliflozin 15 mg com. tablet with food resulted in no meaningful effect on ertugliflozin area under the plasma concn.-time curve (AUC), but decreased peak concns. (Cmax) by 29%. The effect on Cmax is not clin. relevant and ertugliflozin can be administered without regard to food. Mild, moderate, and severe renal impairment were assocd. with a ≤ 70% increase in ertugliflozin exposure relative to subjects with normal renal function, and no dose adjustment in renal impairment patients is needed based on PK results. Consistent with the mechanism of action of SGLT2 inhibitors, 24-h urinary glucose excretion decreased with worsening renal function. In subjects with moderate hepatic impairment, a decrease in AUC (13%) relative to subjects with normal hepatic function was obsd. and not considered clin. relevant. Concomitant administration of metformin, sitagliptin, glimepiride, or simvastatin with ertugliflozin did not have clin. meaningful effects on the PK of ertugliflozin or the coadministered medications. Coadministration of rifampin decreased ertugliflozin AUC and Cmax by 39% and 15%, resp., and is not expected to affect efficacy in a clin. meaningful manner. This comprehensive evaluation supports administration to patients with T2DM without regard to prandial status and with no dose adjustments for coadministration with commonly prescribed drugs, or in patients with renal impairment or mild-to-moderate hepatic impairment based on ertugliflozin PK.
- 151Yan, Q.; Ding, N.; Li, Y. Synthesis and biological evaluation of novel dioxa-bicycle C-arylglucosides as SGLT2 inhibitors. Carbohydr. Res. 2016, 421, 1– 8, DOI: 10.1016/j.carres.2015.10.011[Crossref], [PubMed], [CAS], Google Scholar151https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXitVSqu73J&md5=6dcd4cadbc4d0e537c78b947faa4d9c4Synthesis and biological evaluation of novel dioxa-bicycle C-aryl glucosides as SGLT2 inhibitorsYan, Qi; Ding, Ning; Li, YingxiaCarbohydrate Research (2016), 421 (), 1-8CODEN: CRBRAT; ISSN:0008-6215. (Elsevier Ltd.)A series of novel C-aryl glucosides contg. dioxa-bicycle were synthesized and evaluated for inhibition activity against hSGLT2. Among the compds. tested, compd. I showed moderate SGLT2 inhibition activities at 700 nM. The results could benefit the discovery of new SGLT2 inhibitors.
- 152Rendell, M. S. Sotagliflozin: a combined SGLT1/SGLT2 inhibitor to treat diabetes. Expert Rev. Endocrinol. Metab. 2018, 13, 333– 339, DOI: 10.1080/17446651.2018.1537779[Crossref], [PubMed], [CAS], Google Scholar152https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitVyitb3L&md5=e3f23ce14df92eb05d7cf9e45214ed57Sotagliflozin: a combined SGLT1/SGLT2 inhibitor to treat diabetesRendell, Marc S.Expert Review of Endocrinology & Metabolism (2018), 13 (6), 333-339CODEN: EREMBI; ISSN:1744-6651. (Taylor & Francis Ltd.): Sotagliflozin is the first dual SGLT1/SGLT2 inhibitor developed for use in diabetes. The agent blocks SGLT2 in the kidneys and SGLT1 in the intestines resulting in reduced early phase glucose absorption and increased blood levels of GLP-1. Initial studies were directed at type 1 diabetes.: The published information on sotagliflozin is reviewed, along with the results of several pivotal Type 1 diabetes trials.: Sotagliflozin treatment lowers HbA1c and reduces glucose variability in Type 1 diabetes patients. Several other SGLT2 inhibitors have been assocd. with a tendency to diabetic ketoacidosis (DKA). In the type 1 trials, sotagliflozin treated individuals experienced DKA at a higher rate than placebo treated patients. An addnl. safety concern arises from the as yet unknown potential risks in women of child bearing potential. The sotagliflozin development program has now been extended to trials in type 2 diabetes. In type 2 diabetes, long-term studies will be needed to assess the benefits and risks of the agent as a possible alternative to currently marketed SGLT2 inhibitors.
- 153Li, Y.; Shi, Z.; Chen, L.; Zheng, S.; Li, S.; Xu, B.; Liu, Z.; Liu, J.; Deng, C.; Ye, F. Discovery of a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor (HSK0935) for the treatment of type 2 diabetes. J. Med. Chem. 2017, 60, 4173– 4184, DOI: 10.1021/acs.jmedchem.6b01818[ACS Full Text], [CAS], Google Scholar153https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXmslKktbY%253D&md5=7e35f9d80fd81c48a66934bde89098a0Discovery of a Potent, Selective Renal Sodium-Dependent Glucose Cotransporter 2 (SGLT2) Inhibitor (HSK0935) for the Treatment of Type 2 DiabetesLi, Yao; Shi, Zongjun; Chen, Lei; Zheng, Suxin; Li, Sheng; Xu, Bo; Liu, Zhenhong; Liu, Jianyu; Deng, Chongyang; Ye, FeiJournal of Medicinal Chemistry (2017), 60 (10), 4173-4184CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A new class of potent and highly selective SGLT2 inhibitors is disclosed. Compd. I (HSK0935) demonstrated excellent hSGLT2 inhibition of 1.3 nM and a high hSGLT1/hSGLT2 selectivity of 843-fold. It showed robust urinary glucose excretion in Sprague-Dawley (SD) rats and affected more urinary glucose excretion in Rhesus monkeys. Finally, an efficient synthetic route has been developed featuring a ring-closing cascade reaction to incorporate a double ketal 1-methoxy-6,8-dioxabicyclo[3.2.1]octane ring system.
- 154Wenzel, S. E.; Kamada, A. K. Zileuton: the first 5-lipoxygenase inhibitor for the treatment of asthma. Ann. Pharmacother. 1996, 30, 858– 864, DOI: 10.1177/106002809603000725[Crossref], [PubMed], [CAS], Google Scholar154https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XkvFSnsbw%253D&md5=8e354116ee2cefee87a2c0ff999a2022Zileuton: The first 5-lipoxygenase inhibitor for the treatment of asthmaWenzel, Sally E.; Kamada, Alan K.Annals of Pharmacotherapy (1996), 30 (7/8), 858-864CODEN: APHRER; ISSN:1060-0280. (Harvey Whitney Books Co.)A review with 34 refs. Zileuton, an orally active 5-lipoxygenase inhibitor that represents the first of a new class of medications to be used in the treatment of asthma is described. Zileuton has the ability to attenuate induced bronchospasm, produce some degree of bronchodilation, and provide antiinflammatory or steroid-sparing effects with both single doses (800 mg) and chronic treatment (400 and 600 mg). Zileuton has been studied in patients requiring daily inhaled β-adrenergic agonist treatment; however, data from pediatric populations and comparisons with other asthma medications are limited at this time. Adverse effects include dyspepsia and elevated liver enzymes (incidence ∼ 3%). One case of jaundice has been reported among the more than 5000 patients treated with zileuton. There is also some concern for drug interactions with hepatically cleared medications, such as theophylline.
- 155(a) Delorme, D.; Ducharme, Y.; Brideau, C.; Chan, C. C.; Chauret, N.; Desmarais, S.; Dubé, D.; Falgueyret, J. P.; Fortin, R.; Guay, J.; Hamel, P.; Jones, T. R.; Lépine, C.; Li, C.; McAuliffe, M.; McFarlane, C. S.; Nicoll-Griffith, D. A.; Riendeau, D.; Yergey, J. A.; Girard, Y. Dioxabicyclooctanyl naphthalenenitriles as nonredox 5-lipoxygenase inhibitors: structure-activity relationship study directed toward the improvement of metabolic stability. J. Med. Chem. 1996, 39, 3951– 3970, DOI: 10.1021/jm960301c[ACS Full Text.], [CAS], Google Scholar155ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XlsVekurg%253D&md5=4f1629295def29b1d4115c5cee59036bDioxabicyclooctanyl Naphthalenenitriles as Nonredox 5-Lipoxygenase Inhibitors: Structure-Activity Relationship Study Directed toward the Improvement of Metabolic StabilityDelorme, Daniel; Ducharme, Yves; Brideau, Christine; Chan, Chi-Chung; Chauret, Nathalie; Desmarais, Sylvie; Dube, Daniel; Falgueyret, Jean-Pierre; Fortin, Rejean; et al.Journal of Medicinal Chemistry (1996), 39 (20), 3951-3970CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Naphthalenic lignan lactone I (L-702,539), a potent and selective 5-lipoxygenase (5-LO) inhibitor, is extensively metabolized at two different sites: the tetrahydropyran and the lactone rings. Early knowledge of the metabolic pathways triggered and directed a structure-activity relationship study aimed toward the improvement of metabolic stability in this series. The best modifications discovered, i.e., replacement of the lactone ring by a nitrile group, replacement of the tetrahydropyran ring by a 6,8-dioxabicyclo[3.2.1]octanyl moiety, and replacement of the pendant Ph ring by a 3-furyl ring, were incorporated in a single mol. to produce inhibitor II (L-708,780). II inhibits the oxidn. of arachidonic acid to 5-hydroperoxyeicosatetraenoic acid by 5-LO (IC50 = 190 nM) and the formation of leukotriene B4 in human polymorphonuclear leukocytes (IC50 = 3 nM) as well as in human whole blood (IC50 = 150 nM). The good inhibitory profile shown by naphthalenenitrile II is accompanied by an improved resistance to oxidative metab. In addn., II is orally active in the functional model of antigen-induced bronchoconstriction in allergic squirrel monkeys (95% inhibition at 0.1 mg/kg).(b) Hamel, P.; Riendeau, D.; Brideau, C.; Chan, C.-C.; Desmarais, S.; Delorme, D.; Dube, D.; Ducharme, Y.; Ethier, D.; Grimm, E.; Falgueyret, J.-P.; Guay, J.; Jones, T. R.; Kwong, E.; McFarlane, C. S.; Piechuta, H.; Roumi, M.; Tagari, P.; Young, R. N.; Girard, Y. Substituted (pyridylmethoxy)naphthalenes as potent and orally active 5-lipoxygenase inhibitor. synthesis, biological profile, and pharmacokinetics of L-739,010. J. Med. Chem. 1997, 40, 2866– 2875, DOI: 10.1021/jm970046b[ACS Full Text], [CAS], Google Scholar155bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXlt1Kks7k%253D&md5=2f8e56dac331ebc7293780cc49941971Substituted (Pyridylmethoxy)naphthalenes as Potent and Orally Active 5-Lipoxygenase Inhibitors: Synthesis, Biological Profile, and Pharmacokinetics of L-739,010Hamel, Pierre; Riendeau, Denis; Brideau, Christine; Chan, Chi-Chung; Desmarais, Sylvie; Delorme, Daniel; Dube, Daniel; Ducharme, Yves; Ethier, Diane; Grimm, Erich; Falgueyret, Jean-Pierre; Guay, Jocelyne; Jones, Tom R.; Kwong, Elizabeth; McAuliffe, Malia; McFarlane, Cyril S.; Piechuta, Hanna; Roumi, Marie; Tagari, Philip; Young, Robert N.; Girard, YvesJournal of Medicinal Chemistry (1997), 40 (18), 2866-2875CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Dioxabicyclooctanyl naphthalenenitriles have been reported as a class of potent and nonredox 5-lipoxygenase (5-LO) inhibitors. These bicyclo derivs. were shown to be metabolically more stable than their tetrahydropyranyl counterparts but were not well orally absorbed. Replacement of the Ph ring in the naphthalenenitrile L 708,780 by a pyridine ring leads to the potent and orally absorbed inhibitor 3g (L-739,010, 2-cyano-4-(3-furyl)-7-[[6-[3-(3-hydroxy-6,8-dioxabicyclo[3.2.1]octanyl)]-2-pyridyl]methoxy]naphthalene). Compd. 3g inhibits 5-HPETE prodn. by human 5-LO and LTB4 biosynthesis by human PMN leukocytes and human whole blood (IC50s of 20, 1.6, and 42 nM, resp.). Deriv. 3g is orally active in the rat pleurisy model (inhibition of LTB4, ED50 = 0.3 mg/kg) and in the anesthetized dog model (inhibition of ex vivo whole blood LTB4 and urinary LTE4, ED50 = 0.45 and 0.23 μg/kg/min, resp., i.v. infusion). In addn., 3g shows excellent functional activity against ovalbumin-induced dyspnea in rats (60% inhibition at 0.5 mg/kg, 4 h pretreatment) and Ascaris-induced bronchoconstriction in conscious sheep (50% and >85% inhibition in early and late phases, resp. at 2.5 μg/kg/min, i.v. infusion) and, more particularly in the conscious antigen sensitive squirrel monkey model (53% inhibition of the increase in RL and 76% in the decrease of Cdyn, at 0.1 mg/kg, po). In rats and dogs, 3g presents excellent pharmacokinetics (estd. half-lives of 5 and 16 h, resp.) and bioavailabilities (26% and 73% when dosed as its hydrochloride salt at doses of 20 and 10 mg/kg, resp., in methocel suspension). Based on its overall biol. profile, compd. 3g has been selected for preclin. animal toxicity studies.
- 156(a) Chauret, N.; Nicoll-Griffith, D.; Friesen, R.; Li, C.; Trimble, L.; Dubé, D.; Fortin, R.; Girard, Y.; Yergey, J. Microsomal metabolism of the 5-lipoxygenase inhibitors L-746,530 and L-739,010 to reactive intermediates that covalently bind to protein: the role of the 6,8-dioxabicyclo[3.2.1]octanyl moiety. Drug Metab. Dispos. 1995, 23, 1325– 1334[PubMed], [CAS], Google Scholar.156ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XhvF2gtQ%253D%253D&md5=01f2cd69374a1f921559e5ab49b48fbbMicrosomal metabolism of the 5-lipoxygenase inhibitors L-746,530 and L-739,010 to reactive intermediates that covalently bind to protein: the role of the 6,8-dioxabicyclo[3.2.1]octanyl moietyChauret, N.; Nicoll-Griffith, D.; Friesen, R.; Li, C.; Trimble, L.; Dube, D.; Fortin, R.; Girard, Y.; Yergey, J.Drug Metabolism and Disposition (1995), 23 (12), 1325-34CODEN: DMDSAI; ISSN:0090-9556. (Williams & Wilkins)Hepatic microsomes from different species were used to study the oxidative metab. of L-746,530 and L-739,010, two potent and specific 5-lipoxygenase inhibitors. HPLC anal. of the incubates obtained from the microsomal incubations of L-739,010 and L-746,530 showed only traces of metabolites. However, recovery of the starting material in the supernatant was less than quant. in all of the species studied (∼90% in rat.vtheta. ∼70% in the dexamethasone-induced rat, ∼70-90% in humans, and ∼60% in the rhesus monkey for both compds.). The recovery of the starting material was found to be time- and NADPH-dependent, suggesting that metabolite(s) were formed and reacting with the microsomal proteins. Evidence that the cytochrome P 4503A (CYP3A) contributed to the formation of the reactive metabolite(s) was shown by the low recovery of material that was obsd. upon incubation with microsomes obtained from dexamethasone-treated rats (a CYP3A inducer), compared with microsomes obtained from untreated rats. Also, the recovery of material was improved when troleandomycin, a CYP3A inhibitor, was added to rhesus monkey microsomal incubations (25% more parent compds. detected in the supernatant with 100 μM of troleandomycin). Using radiolabeled L-746,530 and gel electrophoresis anal., it was confirmed that radiolabeled material was covalently bound to the microsomal protein. Incubations of L-739,010 and L-746,530 in the presence of semicarbazide resulted, in both cased, in the formation of two adducts. Using a combination of NMR, liq. second-ion MS, and UV techniques, these adducts were identified as isomers of an oxidized metabolite that had been trapped by semicarbazide. The site of oxidn. was detd. to be on the dioxabicyclo moiety. The importance of this moiety in the formation of reactive metabolite(s) was verified by incubating analogs of the 5-lipoxygenase inhibitors that contained blocking Me groups at the proposed site of oxidn. on the bicyclo moiety. Incubations of these gemdimethyl analogs of L-746,530 and L-739,010 with microsomes from different species resulted in significantly improved recovery of the starting material (∼94% in the rat, 85% in the dexamethasone-induced rat, 95% in humans, and 85% in the rhesus monkey for both compds.) and significantly less radioactive binding to the microsomal protein.(b) Zhang, K. E.; Naue, J. A.; Arison, B.; Vyas, K. P. Microsomal metabolism of the 5-lipoxygenase inhibitor L-739,010: evidence for furan bioactivation. Chem. Res. Toxicol. 1996, 9, 547– 554, DOI: 10.1021/tx950183g[ACS Full Text], [CAS], Google Scholar156bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28Xpt1agsw%253D%253D&md5=3f25fc32090372817fd7d247c2dc2910Microsomal Metabolism of the 5-Lipoxygenase Inhibitor L-739,010: Evidence for Furan BioactivationZhang, Kanyin E.; Naue, Jeanne A.; Arison, Byron; Vyas, Kamlesh P.Chemical Research in Toxicology (1996), 9 (2), 547-54CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)The novel 5-lipoxygenase inhibitor 3-cyano-1-(3-furyl)-6-{[6-(3α-hydroxy-6,8-dioxabicyclo[3.2.1]octanyl)pyridin-2-yl]methoxyl}naphthalene (L-739,010), when administered to rats and rhesus monkeys, was found to produce metabolites which appeared to be covalently bound to plasma proteins. Incubation of [14C]L-739,010 with rat liver microsomes did not yield appreciable amts. of sol. metabolites but resulted in covalent binding to microsomal proteins. The covalent binding was NADPH-dependent and was enhanced by 1.5- and 2-fold when rats were pretreated with phenobarbital and dexamethasone, resp. Addn. of triacetyloleandomycin and diethyldithiocarbamate to the incubation mixt. inhibited the covalent binding by 60% and 46%, resp. These findings suggest that the cytochrome P 450 3A family of enzymes play an important role in the bioactivation of L-739,010. The presence of GSH attenuated the covalent binding by 50%, while methoxylamine, an aldehyde trapping agent, blocked the covalent binding completely and, concurrently, produced several sol. metabolic adducts. Subsequently, major methoxylamine adducts were identified by LC-MS/MS and NMR as O-methyloximes of the ring-opened furan moiety of L-739,010. Incubation of L-739,010 with methoxylamine and hepatic microsomes from dog, rhesus monkey, and human produced similar metabolic adducts as those formed by rat liver microsomes. Therefore, under these exptl. conditions, the furan moiety, which undergoes oxidative cleavage to the highly reactive 2-butene-1,4-dialdehyde, represents the major site of L-739,010 biotransformation. This putative reactive intermediate could react with microsomal proteins in vitro and physiol. proteins in vivo. Since furan bioactivation is believed to be responsible for the toxicity of many furan-contg. compds., the furan moiety of L-739,010 may be regarded as undesirable.
- 157Ohtake, Y.; Sato, T.; Kobayashi, T.; Nishimoto, M.; Taka, N.; Takano, K.; Yamamoto, K.; Ohmori, M.; Yamaguchi, M.; Takami, K.; Yeu, S.; Ahn, K.; Matsuoka, H.; Morikawa, K.; Suzuki, M.; Hagita, H.; Ozawa, K.; Yamaguchi, K.; Kato, M.; Ikeda, S. Discovery of tofogliflozin, a novel C-arylglucoside with an O-spiroketal ring system, as a highly selective sodium glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes. J. Med. Chem. 2012, 55, 7828– 7840, DOI: 10.1021/jm300884k[ACS Full Text], [CAS], Google Scholar157https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtFOrurfN&md5=174a0538c13a286dd320a52395e1dd85Discovery of Tofogliflozin, a Novel C-Arylglucoside with an O-Spiroketal Ring System, as a Highly Selective Sodium Glucose Cotransporter 2 (SGLT2) Inhibitor for the Treatment of Type 2 DiabetesOhtake, Yoshihito; Sato, Tsutomu; Kobayashi, Takamitsu; Nishimoto, Masahiro; Taka, Naoki; Takano, Koji; Yamamoto, Keisuke; Ohmori, Masayuki; Yamaguchi, Marina; Takami, Kyoko; Yeu, Sang-Yong; Ahn, Koo-Hyeon; Matsuoka, Hiroharu; Morikawa, Kazumi; Suzuki, Masayuki; Hagita, Hitoshi; Ozawa, Kazuharu; Yamaguchi, Koji; Kato, Motohiro; Ikeda, SachiyaJournal of Medicinal Chemistry (2012), 55 (17), 7828-7840CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Inhibition of sodium glucose cotransporter 2 (SGLT2) has been proposed as a novel therapeutic approach to treat type 2 diabetes. In our efforts to discover novel inhibitors of SGLT2, we first generated a 3D pharmacophore model based on the superposition of known inhibitors. A search of the Cambridge Structural Database using a series of pharmacophore queries led to the discovery of an O-spiroketal C-arylglucoside scaffold. Subsequent chem. examn. combined with computational modeling resulted in the identification of the clin. candidate CSG452 (tofogliflozin), which is currently under phase III clin. trials.
- 158(a) Lv, B.; Xu, B.; Feng, Y.; Peng, K.; Xu, G.; Du, J.; Zhang, L.; Zhang, W.; Zhang, T.; Zhu, L.; Ding, H.; Sheng, Z.; Welihinda, A.; Seed, B.; Chen, Y. Exploration of O-spiroketal C-arylglucosides as novel and selective renal sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors. Bioorg. Med. Chem. Lett. 2009, 19, 6877– 6881, DOI: 10.1016/j.bmcl.2009.10.088[Crossref], [PubMed], [CAS], Google Scholar.158ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsVWht7vJ&md5=9b7461b86601f207bd56759152b5ae4cExploration of O-spiroketal C-aryl-glucosides as novel and selective renal sodium-dependent glucose co-transporter 2 (SGLT2) inhibitorsLv, Binhua; Xu, Baihua; Feng, Yan; Peng, Kun; Xu, Ge; Du, Jiyan; Zhang, Lili; Zhang, Wenbin; Zhang, Ting; Zhu, Liangcheng; Ding, Haifeng; Sheng, Zelin; Welihinda, Ajith; Seed, Brian; Chen, YuanweiBioorganic & Medicinal Chemistry Letters (2009), 19 (24), 6877-6881CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A series of novel O-spiroketal C-aryl-glucosides, e.g. I, have been prepd. and evaluated in cell-based functional assays for activity against human sodium-dependent glucose co-transporters 1 and 2 (SGLT1 and SGLT2). The core spiro[iso-benzofuran-1,2'-pyran] structure proved to be an effective scaffold for diversification and a no. of compds. with single digit nano-molar potency and high selectivity have been synthesized. Compd. I promoted glucosuria when administered in vivo in rats and produced a significant blood glucose redn. effect.(b) Kasahara-Ito, N.; Fukase, H.; Ogama, Y.; Saito, T.; Ohba, Y.; Shimada, S.; Takano, Y.; Ichihara, T.; Terao, K.; Nakamichi, N.; Kumagai, Y.; Ikeda, S. Pharmacokinetics and pharmacodynamics of tofogliflozin (a selective SGLT2 inhibitor) in healthy male subjects. Drug Res. 2017, 67, 349– 357, DOI: 10.1055/s-0043-104779[Crossref], [CAS], Google Scholar158bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXmtlOqur8%253D&md5=6dde4f95f62682a817b5aa9e5268dacdPharmacokinetics and Pharmacodynamics of Tofogliflozin (a Selective SGLT2 Inhibitor) in Healthy Male SubjectsKasahara-Ito, Nahoko; Fukase, Hiroyuki; Ogama, Yoichiro; Saito, Tomohisa; Ohba, Yasuhiro; Shimada, Sumire; Takano, Yasuki; Ichihara, Tomoko; Terao, Kimio; Nakamichi, Noboru; Kumagai, Yuji; Ikeda, SachiyaDrug Research (Stuttgart, Germany) (2017), 67 (6), 349-357CODEN: DRSGAO; ISSN:2194-9379. (Georg Thieme Verlag)Purpose: Tofogliflozin is a selective oral inhibitor of sodium-glucose co-transporter 2 for treatment of type 2 diabetes mellitus. The pharmacokinetics, pharmacodynamics, and safety of tofogliflozin were investigated in healthy male subjects. Methods: Three studies were conducted: single-ascending dose study (10-640 mg) in 56 Japanese and 24 Caucasian subjects; multiple-ascending dose study (2.5-80 mg once daily for 7 days) in 24 Japanese subjects; and food-effect study (20-40 mg) in 30 Japanese subjects. Results: Tofogliflozin was absorbed rapidly and eliminated from the systemic circulation with a t1/2 of 5-6 h. Exposure increased dose-proportionally up to 320 mg. Body wt.-cor. exposure was similar between Japanese and Caucasian subjects. Urinary excretion of tofogliflozin ranged from 17.1 to 27.4% of dose. Tofogliflozin did not accumulate with once daily administration. Food intake decreased Cmax by approx. 30% but did not change AUC0-inf. Tofogliflozin caused dose-dependent daily urinary glucose excretion (UGE0-24h), but food intake condition at administration did not affect it. The exposure-response relationship between plasma av. concn. of tofogliflozin (Cavg) and UGE0-24h fitted Emax model well. There were no serious adverse events leading to discontinuation or episodes of hypoglycemia. Conclusions: Single and multiple administration of tofogliflozin were generally well tolerated. Exposure to tofogliflozin was dose-proportional up to 320 mg and did not accumulate with multiple once-a-day administration. The model suggests more than 100 ng/mL Cavg corresponding to the dose of between 20 and 40 mg leads to almost max. effect of tofogliflozin.
- 159(a) Seward, E. M.; Carlson, E.; Harrison, T.; Haworth, K. E.; Herbert, R.; Kelleher, F. J.; Kurtz, M. M.; Moseley, J.; Owen, S. N.; Owens, A. P.; Sadowski, S. J.; Swain, C. J.; Williams, B. J. Spirocyclic NK1 antagonists I: [4.5] and [5.5]-spiroketals. Bioorg. Med. Chem. Lett. 2002, 12, 2515– 2518, DOI: 10.1016/S0960-894X(02)00506-1[Crossref], [PubMed], [CAS], Google Scholar.159ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XmsVWju74%253D&md5=cb0865b5cb065e3c39b875f0a290b9deSpirocyclic NK1 antagonists I: [4.5] and [5.5]-SpiroketalsSeward, Eileen M.; Carlson, Emma; Harrison, Timothy; Haworth, Karen E.; Herbert, Richard; Kelleher, Fintan J.; Kurtz, Marc M.; Moseley, Jonathan; Owen, Simon N.; Owens, Andrew P.; Sadowski, Sharon J.; Swain, Christopher J.; Williams, Brian J.Bioorganic & Medicinal Chemistry Letters (2002), 12 (18), 2515-2518CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)A series of novel spiroketal-based NK1 antagonists is described. The effect of modifications to the spiroether ring and arom. substituents are discussed, leading to the identification of compds. with high affinity and excellent CNS penetration.(b) Quach, R.; Furkert, D. P.; Brimble, M. A. Gold Catalysis: Synthesis of Spiro, Bridged, and Fused Ketal Natural Products. Org. Biomol. Chem. 2017, 15, 3098– 3104, DOI: 10.1039/C7OB00496F[Crossref], [PubMed], [CAS], Google Scholar.159bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXktVSgsro%253D&md5=7a55273502ceac5b0e77e680043750b9Gold catalysis: synthesis of spiro, bridged, and fused ketal natural productsQuach, Rachelle; Furkert, Daniel P.; Brimble, Margaret A.Organic & Biomolecular Chemistry (2017), 15 (15), 3098-3104CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)A review. In the last decade the use of homogeneous gold catalysts has rapidly grown and become a valuable tool for complex natural product synthesis. Spiroketal natural products are valuable targets for total synthesis and medicinal chem. applications. The use of gold catalysts has emerged as a useful tool to synthesize these privileged scaffolds. This review summarizes the application of gold catalysis for the syntheses of spiro, bridged and fused ketal natural products.(c) Choi, K. W.; Brimble, M. A. Synthesis of spiroacetal-nucleosides as privileged natural product-like scaffolds. Org. Biomol. Chem. 2009, 7, 1424– 36, DOI: 10.1039/b818314g[Crossref], [PubMed], [CAS], Google Scholar.159chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXjtlOiurs%253D&md5=7acf90ce72ff7047bb66cad9f363f9b0Synthesis of spiroacetal-nucleosides as privileged natural product-like scaffoldsChoi, Ka Wai; Brimble, Margaret A.Organic & Biomolecular Chemistry (2009), 7 (7), 1424-1436CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)The elaboration of a 6,6-spiroacetal scaffold to incorporate a nucleoside unit at the anomeric position is described. The novel spiroacetal-nucleoside hybrids, e.g. I, were generated via nucleosidation of acetoxy-spiroacetal with a series of silylated nucleobases under Vorbrueggen conditions.(d) Zhang, F. M.; Zhang, S. Y.; Tu, Y. Q. Recent progress in the isolation, bioactivity, biosynthesis, and total synthesis of natural spiroketals. Nat. Prod. Rep. 2018, 35, 75– 104, DOI: 10.1039/C7NP00043J[Crossref], [PubMed], [CAS], Google Scholar.159dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtlOktLc%253D&md5=9103edde941b264841c85c5f5ee2bdc7Recent progress in the isolation, bioactivity, biosynthesis, and total synthesis of natural spiroketalsZhang, Fu-Min; Zhang, Shu-Yu; Tu, Yong-QiangNatural Product Reports (2018), 35 (1), 75-104CODEN: NPRRDF; ISSN:0265-0568. (Royal Society of Chemistry)A review on. Spiroketal (spiroacetal), a common moiety in numerous natural products, drugs and functional mols., has been a central topic in org. chem. for a long time. Owing to their structural diversity, important bioactivity and functional irreplaceability, natural spiroketals have attracted the interest of natural product chemists, medical chemists, biol. chemists, agricultural chemists, synthetic chemists, and chem. biologists. In this review, we focus on the overview of the isolation, bioactivity, biosynthesis and total synthesis of spiroketals from 2011 to July 2017.(e) Lenci, E. Synthesis and biological properties of spiroacetal-containing small molecules. Small Molecule Drug Discovery 2020, 225– 245, DOI: 10.1016/B978-0-12-818349-6.00008-X
- 160(a) Ghosh, A. K.; Dawson, Z. L.; Mitsuya, H. Darunavir, a conceptually new HIV-1 protease inhibitor for the treatment of drug-resistant HIV. Bioorg. Med. Chem. 2007, 15, 7576– 7580, DOI: 10.1016/j.bmc.2007.09.010[Crossref], [PubMed], [CAS], Google Scholar.160ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtF2msL%252FJ&md5=56aa3f9486e422657e4da60cd6f0c526Darunavir, a conceptually new HIV-1 protease inhibitor for the treatment of drug-resistant HIVGhosh, Arun K.; Dawson, Zachary L.; Mitsuya, HiroakiBioorganic & Medicinal Chemistry (2007), 15 (24), 7576-7580CODEN: BMECEP; ISSN:0968-0896. (Elsevier Ltd.)Our structure-based design strategies which specifically target the HIV-1 protease backbone, resulted in a no. of exceedingly potent nonpeptidyl inhibitors. One of these inhibitors, darunavir (TMC114), contains a privileged, structure-based designed high-affinity P2 ligand, 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane (bis-THF). Darunavir has recently been approved for the treatment of HIV/AIDS patients harboring multidrug-resistant HIV-1 variants that do not respond to previously existing HAART regimens.(b) Ghosh, A. K.; Sridhar, P. R.; Kumaragurubaran, N.; Koh, Y.; Weber, I. T.; Mitsuya, H. Bis-tetrahydrofuran: a privileged ligand for darunavir and a new generation of HIV protease inhibitors that combat drug resistance. ChemMedChem 2006, 1, 939– 950, DOI: 10.1002/cmdc.200600103[Crossref], [PubMed], [CAS], Google Scholar.160bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXjsVCmu7w%253D&md5=e9826330e807476b916d69e86ff55a40Bis-tetrahydrofuran: a privileged ligand for darunavir and a new generation of HIV protease inhibitors that combat drug resistanceGhosh, Arun K.; Sridhar, Perali Ramu; Kumaragurubaran, Nagaswamy; Koh, Yasuhiro; Weber, Irene T.; Mitsuya, HiroakiChemMedChem (2006), 1 (9), 939-950CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. The structure-based design of bis-tetrahydrofuranyl urethane has emerged as a privileged nonpeptide P2 ligand for a variety of highly potent HIV-1 protease inhibitors. Incorporation of this ligand provided HIV protease inhibitors with exceedingly potent antiviral activity and superior activity against multi-PI-resistant variants relative to other FDA-approved PIs. Recently, TMC-114 (darunavir) was approved by the FDA for treatment of drug-resistant HIV. GW640385 (brecanavir), which incorporates bis-THF as the P2 ligand, is currently in Phase-III clin. development. The bis-THF ligand was specifically designed to fill in the hydrophobic S2 pocket effectively and to promote extensive hydrogen bonding with the protein backbone in the enzyme S2 site. The protein-ligand x-ray crystal structures with TMC-114 and other inhibitors with the bis-THF ligand revealed extensive interactions with the backbone of residues Asp29 and Asp30 at the S2 site. The current design concept targeting the protein backbone may serve as an important guide to combat drug resistance. Further design and synthesis of conceptually novel inhibitors are in progress.(c) Ghosh, A. K. Harnessing nature’s Insight: design of aspartyl protease inhibitors from treatment of drug-resistant HIV to Alzheimer’s disease. J. Med. Chem. 2009, 52, 2163– 2176, DOI: 10.1021/jm900064c[ACS Full Text], [CAS], Google Scholar160chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXktVSlsb0%253D&md5=27bc9377ab9cefffb9c009cc08a6faabHarnessing Nature's Insight: Design of Aspartyl Protease Inhibitors from Treatment of Drug-Resistant HIV to Alzheimer's DiseaseGhosh, Arun K.Journal of Medicinal Chemistry (2009), 52 (8), 2163-2176CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review discussing development of drugs based on synthesis of compds. related to naturally occurring mols. A research program was initiated in 1994 aimed at synthesizing bioactive natural products with interesting structural features. This endeavor resulted in the total synthesis of numerous targets, covering over two dozen or so different structural families. Some notable examples of accomplished bioactive targets include novel and exceedingly potent microtubule stabilizing agents laulimalide and peloruside A; a potent microtubule destabilizing agent cryptophycin 52; anticancer agents amphidinolide T, amphidinolide W, and lasonolide A; antibiotic agent madumycin II; pancreatic lipase inhibitor tetrahydrolipstatin; novel actin inhibitory agents doliculide and jasplakinolide; novel antibacterial agent platensimycin; and a histone deacetylase inhibitor largazole. The unique structural features of these natural products required the development of new synthetic tools and methodologies for their synthesis. In the context of our synthesis of various bioactive targets, a variety of new and practical asym. reactions were developed based on intermol. and intramol. metal chelation. Notable carbon-carbon bond forming synthetic methodologies include highly diastereoselective syn- and anti-aldol reactions, asym. inter- and intramol. Diels-Alder and hetero Diels-Alder reactions, and asym. multicomponent reactions. The scope and utility of these methodologies have been demonstrated through the synthesis of a variety of bioactive mols. Another important objective of our synthetic endeavors is to carry out detailed biol. studies and explore the medicinal potential of these target mols. This crossover, to focus on the biol. aspects of these natural products has led to a no. of unexpected but very significant results.
- 161Vermeir, M.; Lachau-Durand, S.; Mannens, G.; Cuyckens, F.; van Hoof, B.; Raoof, A. Absorption, metabolism, and excretion of darunavir, a new protease inhibitor, administered alone and with low-dose ritonavir in healthy subjects. Drug Metab. Dispos. 2009, 37, 809– 820, DOI: 10.1124/dmd.108.024109[Crossref], [PubMed], [CAS], Google Scholar161https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXktVSku7Y%253D&md5=a7a4d7e5531622b8cfc20a3be8b1d061Absorption, metabolism, and excretion of darunavir, a new protease inhibitor, administered alone and with low-dose ritonavir in healthy subjectsVermeir, Marc; Lachau-Durand, Sophie; Mannens, Geert; Cuyckens, Filip; van Hoof, Bart; Raoof, ArazDrug Metabolism and Disposition (2009), 37 (4), 809-820CODEN: DMDSAI; ISSN:0090-9556. (American Society for Pharmacology and Experimental Therapeutics)Absorption, metab., and excretion of darunavir, an inhibitor of human immunodeficiency virus protease, was studied in eight healthy male subjects after a single oral dose of 400 mg of [14C]-darunavir given alone (unboosted subjects) or with ritonavir [100 mg b.i.d. 2 days before and 7 days after darunavir administration (boosted subjects)]. Plasma exposure to darunavir was 11-fold higher in boosted subjects. Total recoveries of radioactivity in urine and feces were 93.9 and 93.5% of administered radioactivity in unboosted and boosted subjects, resp. The most radio-activity was recovered in feces (81.7% in unboosted subjects and 79.5% in boosted subjects, compared with 12.2 and 13.9% recovered in urine, resp.). Darunavir was extensively metabolized in unboosted subjects, mainly by carbamate hydrolysis, iso-Bu aliph. hydroxylation, and aniline arom. hydroxylation and to a lesser extent by benzylic arom. hydroxylation and glucuronidation. Total excretion of unchanged darunavir accounted for 8.0% of the dose in unboosted subjects. Boosting with ritonavir resulted in significant inhibition of carbamate hydrolysis, iso-Bu aliph. hydroxylation, and aniline arom. hydroxylation but had no effect on arom. hydroxylation at the benzylic moiety, whereas excretion of glucuronide metabolites was markedly increased but still represented a minor pathway. Total excretion of unchanged darunavir accounted for 48.8% of the administered dose in boosted subjects as a result of the inhibition of darunavir metab. by ritonavir. Unchanged darunavir in urine accounted for 1.2% of the administered dose in unboosted subjects and 7.7% in boosted subjects, indicating a low renal clearance. Darunavir administered alone or with ritonavir was well tolerated.
- 162Sadler, B. M.; Chittick, G. E.; Polk, R. E.; Slain, D.; Kerkering, T. M.; Studenberg, S. D.; Lou, Y.; Moore, K. H.; Woolley, J.; Stein, D. S. Metabolic disposition and pharmacokinetics of [14C]-amprenavir, a human immunodeficiency virus type 1 (HIV-1) protease inhibitor, administered as a single oral dose to healthy male subjects. J. Clin. Pharmacol. 2001, 41, 386– 396, DOI: 10.1177/00912700122010249[Crossref], [PubMed], [CAS], Google Scholar162https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXivVGkt78%253D&md5=93d9ef0b96949959c2d85f7427c58951Metabolic disposition and pharmacokinetics of [14C]-amprenavir, a human immunodeficiency virus type 1 (HIV-1) protease inhibitor, administered as a single oral dose to healthy male subjectsSadler, Brian M.; Chittick, Gregory E.; Polk, Ronald E.; Slain, Douglas; Kerkering, Thomas M.; Studenberg, Scott D.; Lou, Yu; Moore, Katy H. P.; Woolley, Joseph L.; Stein, Daniel S.Journal of Clinical Pharmacology (2001), 41 (4), 386-396CODEN: JCPCBR; ISSN:0091-2700. (Sage Publications)The objective of this study was to det. the metabolic profile, routes of elimination, and total recovery of amprenavir and its metabolites after a single oral dose of [14C]-amprenavir. Six healthy male subjects each received a single oral 630 mg dose of amprenavir contg. 95.76 μCi of [14C]-amprenavir in this Phase I mass balance study. The metabolic disposition of amprenavir was detd. through analyses of radiocarbon in whole blood, plasma, urine, and stool samples, collected for a period of 10 to 17 days postdosing. Cerebral spinal fluid (CSF) sampling was conducted on day 1. The ratio of unchanged amprenavir AUC0→∞ to plasma radiocarbon was 27%, suggesting that most of the radiocarbon was metabolites. The median total recovery of the administered dose of radiocarbon was 89% (range: 66%-93%), with 75% (range: 56%-80%) recovered in the feces and 14% (range: 10%-17%) in the urine. Most of the recovered radiocarbon in the feces and urine was excreted within 240 and 48 h postdose, resp. Of the 75% of the radiocarbon dose recovered in the feces, 62% was identified as a metabolite resulting from dioxidn. of the THF ring (GW549445X) and 32% as a metabolite resulting from subsequent oxidn. of the p-aniline sulfonate group (GW549444X). Unchanged amprenavir was below the limit of quantitation in feces and urine. Therefore, approx. 94% of the dose excreted in the feces was accounted for by these two metabolites. Concns. of radiocarbon in the CSF were below the limit of quantitation in 5 of 6 subjects sampled. In summary, oral amprenavir is extensively metabolized in humans, with concns. of unchanged drug below the limits of quantitation in urine and feces. The majority (75%) of administered radiocarbon was excreted in feces.
- 163(a) Ghosh, A. K.; Xu, C.; Rao, K. V.; Baldridge, A.; Agniswamy, J.; Wang, Y.; Weber, I. T.; Aoki, M.; Miguel, S.; Amano, M.; Mitsuya, H. Probing multidrug-resistance and protein-ligand interactions with oxatricyclic designed ligands in HIV-1 protease inhibitors. ChemMedChem 2010, 5, 1850– 1854, DOI: 10.1002/cmdc.201000318[Crossref], [PubMed], [CAS], Google Scholar.163ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtlClu7vM&md5=6f5b753c82f353959b720ecfc550136dProbing Multidrug-Resistance and Protein-Ligand Interactions with Oxatricyclic Designed Ligands in HIV-1 Protease InhibitorsGhosh, Arun K.; Xu, Chun-Xiao; Rao, Kalapala Venkateswara; Baldridge, Abigail; Agniswamy, Johnson; Wang, Yuan-Fang; Weber, Irene T.; Aoki, Manabu; Miguel, Salcedo Gomez Pedro; Amano, Masayuki; Mitsuya, HiroakiChemMedChem (2010), 5 (11), 1850-1854CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)Design and synthesis of HIV-1 protease inhibitor GRL-0519A and its crystal structure with HIV1 protease is investigated.(b) Zhang, H.; Wang, Y.; Shen, C.; Agniswamy, J.; Rao, K. V.; Xu, C.; Ghosh, A. K.; Harrison, R. W.; Weber, I. T. Novel P2 tris-tetrahydrofuran group in antiviral compound 1 (GRL0519) fills the S2 binding pocket of selected mutants of HIV-1 protease. J. Med. Chem. 2013, 56, 1074– 1083, DOI: 10.1021/jm301519z[ACS Full Text.], [CAS], Google Scholar163bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXkt1yhtg%253D%253D&md5=85fbfa86a8f494f6d4925ecf336610afNovel P2 Tris-tetrahydrofuran Group in Antiviral Compound 1 (GRL-0519) Fills the S2 Binding Pocket of Selected Mutants of HIV-1 ProteaseZhang, Hongmei; Wang, Yuan-Fang; Shen, Chen-Hsiang; Agniswamy, Johnson; Rao, Kalapala Venkateswara; Xu, Chun-Xiao; Ghosh, Arun K.; Harrison, Robert W.; Weber, Irene T.Journal of Medicinal Chemistry (2013), 56 (3), 1074-1083CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)GRL-0519 is a potent antiviral inhibitor of HIV-1 protease (PR) possessing tris-tetrahydrofuran (tris-THF) at P2. The high resoln. X-ray crystal structures of inhibitor in complexes with single substitution mutants PRR8q, PRD30N, PRI50V, PRI54M, and PRV82A were analyzed in relation to kinetic data. The smaller valine side chain in PRI50V eliminated hydrophobic interactions with inhibitor and the other subunit consistent with 60-fold worse inhibition. Asn30 in PRD30N showed altered interactions with neighboring residues and 18-fold worse inhibition. Mutations V82A and I54M showed compensating structural changes consistent with 6-7-fold lower inhibition. Gln8 in PRR8q replaced the ionic interactions of wild type Arg8 with hydrogen bond interactions without changing the inhibition significantly. The carbonyl oxygen of Gly48 showed two alternative conformations in all structures likely due to the snug fit of the large tris-THF group in the S2 subsite in agreement with high antiviral efficacy of 1 on resistant virus.(c) Ghosh, A. K.; Rao, K. V.; Nyalapatla, P. R.; Osswald, H. L.; Martyr, C. D.; Aoki, M.; Hayashi, H.; Agniswamy, J.; Wang, Y.; Bulut, H.; Das, D.; Weber, I. T.; Mitsuya, H. Design and development of highly potent HIV-1 protease inhibitors with a crown-like oxotricyclic core as the P2-ligand to combat multidrug-resistant HIV variants. J. Med. Chem. 2017, 60, 4267– 4278, DOI: 10.1021/acs.jmedchem.7b00172[ACS Full Text], [CAS], Google Scholar163chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXmtFKlsLw%253D&md5=03b84db839ddd5d19195e5dd8bf43642Design and Development of Highly Potent HIV-1 Protease Inhibitors with a Crown-Like Oxotricyclic Core as the P2-Ligand To Combat Multidrug-Resistant HIV VariantsGhosh, Arun K.; Rao, Kalapala Venkateswara; Nyalapatla, Prasanth R.; Osswald, Heather L.; Martyr, Cuthbert D.; Aoki, Manabu; Hayashi, Hironori; Agniswamy, Johnson; Wang, Yuan-Fang; Bulut, Haydar; Das, Debananda; Weber, Irene T.; Mitsuya, HiroakiJournal of Medicinal Chemistry (2017), 60 (10), 4267-4278CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Design, synthesis, and evaluation of a new class of exceptionally potent HIV-1 protease inhibitors is reported. Inhibitor I displayed superior antiviral activity and drug-resistance profiles. In fact, this inhibitor showed several orders of magnitude improved antiviral activity over the FDA approved drug, darunavir. This inhibitor incorporates an unprecedented 6-5-5 ring-fused crown-like tetrahydropyranofuran as the P2 ligand and an aminobenzothiazole as the P2' ligand with the (R)-hydroxyethylsulfonamide isostere. The crown-like P2 ligand for this inhibitor has been synthesized efficiently in an optically active form using a chiral Diels-Alder catalyst providing a key intermediate in high enantiomeric purity. Two high resoln. X-ray structures of inhibitor-bound HIV-1 protease revealed extensive interactions with the backbone atoms of HIV-1 protease and provided mol. insight into the binding properties of these new inhibitors.
- 164(a) Chang, Z. The discovery of Qinghaosu (artemisinin) as an effective anti-malaria drug: A unique China story. Sci. China: Life Sci. 2016, 59, 81– 88, DOI: 10.1007/s11427-015-4988-z[Crossref], [PubMed], [CAS], Google Scholar.164ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28vpvVynuw%253D%253D&md5=577bcc8d1c235623b7c436325f7227a2The discovery of Qinghaosu (artemisinin) as an effective anti-malaria drug: A unique China storyChang ZengyiScience China. Life sciences (2016), 59 (1), 81-8 ISSN:.There is no expanded citation for this reference.(b) Cui, L.; Su, X. Discovery, mechanisms of action and combination therapy of artemisinin. Expert Rev. Anti-Infect. Ther. 2009, 7, 999– 1013, DOI: 10.1586/eri.09.68[Crossref], [PubMed], [CAS], Google Scholar.164bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXht1Wru7fM&md5=29fb8392d6b533f4073e958eab1fe1f9Discovery, mechanisms of action and combination therapy of artemisininCui, Li-Wang; Su, Xin-ZhuanExpert Review of Anti-Infective Therapy (2009), 7 (8), 999-1013CODEN: ERATCK; ISSN:1478-7210. (Expert Reviews Ltd.)A review. Despite great international efforts, malaria still inflicts an enormous toll on human lives, esp. in Africa. Throughout history, antimalarial medicines have been one of the most powerful tools in malaria control. However, the acquisition and spread of parasite strains that are resistant to multiple antimalarial drugs have become one of the greatest challenges to malaria treatment, and are assocd. with the increase in morbidity and mortality in many malaria-endemic countries. To deal with this grave situation, artemisinin-based combinatory therapies (ACTs) have been introduced and widely deployed in malarious regions. Artemisinin is a new class of antimalarial compds. discovered by Chinese scientists from the sweet wormwood Artemisia annua. The potential development of resistance to artemisinins by Plasmodium falciparum threatens the usable lifespan of ACTs, and therefore is a subject of close surveillance and extensive research. Studies at the Thai-Cambodian border, a historical epicenter of multidrug resistance, have detected reduced susceptibility to artemisinins as manifested by prolonged parasite-clearance times, raising considerable concerns on resistance development. Despite this significance, there is still controversy on the mode of action of artemisinins. Although a no. of potential cellular targets of artemisinins have been proposed, they remain to be verified exptl. Here, we review the history of artemisinin discovery, discuss the mode of action and potential drug targets, and present strategies to elucidate resistance mechanisms.(c) Fernández-Álvaro, E.; Hong, W. D.; Nixon, G. L.; O’Neill, P. M.; Calderón, F. Antimalarial chemotherapy: natural product inspired development of preclinical and clinical candidates with diverse mechanisms of action. J. Med. Chem. 2016, 59, 5587– 5603, DOI: 10.1021/acs.jmedchem.5b01485[ACS Full Text.], [CAS], Google Scholar164chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xht1aht7Y%253D&md5=993e5139a177a86e47dff4330b986bffAntimalarial Chemotherapy: Natural Product Inspired Development of Preclinical and Clinical Candidates with Diverse Mechanisms of ActionFernandez-Alvaro, Elena; Hong, W. David; Nixon, Gemma L.; O'Neill, Paul M.; Calderon, FelixJournal of Medicinal Chemistry (2016), 59 (12), 5587-5603CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Natural products have played a pivotal role in malaria chemotherapy progressing from quinine and artemisinin to ozonide-based compds. Many of these natural products have served as template for the design and development of antimalarial drugs currently in the clinic or in the development phase. In this review, we will detail those privileged scaffolds that have guided medicinal chem. efforts yielding mols. that have reached the clinic.(d) Wells, T. N.; Huijsduijnen, R. H.; Voorhis, W. C. Malaria medicines: a glass half full?. Nat. Rev. Drug Discovery 2015, 14, 424– 442, DOI: 10.1038/nrd4573[Crossref], [PubMed], [CAS], Google Scholar.164dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFemsbvM&md5=43f35590f86c240a4150b5cb4f5670adMalaria medicines: a glass half full?Wells, Timothy N. C.; Hooft van Huijsduijnen, Rob; Van Voorhis, Wesley C.Nature Reviews Drug Discovery (2015), 14 (6), 424-442CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)A review. Despite substantial scientific progress over the past two decades, malaria remains a worldwide burden that causes hundreds of thousands of deaths every year. New, affordable and safe drugs are required to overcome increasing resistance against artemisinin-based treatments, treat vulnerable populations, interrupt the parasite life cycle by blocking transmission to the vectors, prevent infection and target malaria species that transiently remain dormant in the liver. In this Review, we discuss how the antimalarial drug discovery pipeline has changed over the past 10 years, grouped by the various target compd. or product profiles, to assess progress and gaps, and to recommend priorities.(e) Sharma, B.; Singh, P.; Singh, A. K.; Awasthi, S. K. Advancement of chimeric hybrid drugs to cure malaria infection: an overview with special emphasis on endoperoxide pharmacophores. Eur. J. Med. Chem. 2021, 219, 113408, DOI: 10.1016/j.ejmech.2021.113408[Crossref], [PubMed], [CAS], Google Scholar164ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhtFShu7fP&md5=5372f0027e4ac4114d766bc725be222eAdvancement of chimeric hybrid drugs to cure malaria infection: An overview with special emphasis on endoperoxide pharmacophoresSharma, Bhawana; Singh, Preeti; Singh, Ashawani Kumar; Awasthi, Satish K.European Journal of Medicinal Chemistry (2021), 219 (), 113408CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)Emergence and spread of Plasmodium falciparum resistant to artemisinin-based combination therapy has led to a situation of haste in the scientific and pharmaceutical communities. Sincere efforts are redirected towards finding alternative chemotherapeutic agents that are capable of combating multidrug-resistant parasite strains. Extensive research yielded the concept of "Chimeric Bitherapy (CB)" which involves the linking of two mols. with individual pharmacol. activity and exhibit dual mode of action into a single hybrid mol. Current research in this field seems to endorse hybrid mols. as the next-generation antimalarial drugs and are more effective compared to the multi-component drugs because of the lower occurrence of drug-drug adverse effects. This review is an attempt to congregate complete survey on endoperoxide based hybrid antiplasmodial mols. that will give glimpse on the future directions for successful development and discovery of useful antimalarial hybrid drugs.
- 165(a) Zeng, M.; Li, L.; Chen, S.; Li, C.; Liang, X.; Chen, M.; Clardy, J. Chemical transformations of qinghaosu, a peroxidic antimalarial. Tetrahedron 1983, 39, 2941– 2946, DOI: 10.1016/S0040-4020(01)92155-6[Crossref], [CAS], Google Scholar.165ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL2cXmtFym&md5=0a457679a176c87a49346bc6ac347effChemical transformations of qinghaosu, a peroxidic antimalarialZeng, Meiyi; Li, Lanna; Chen, Shufeng; Li, Guangyi; Liang, Xiaotian; Chen, Marie; Clardy, JonTetrahedron (1983), 39 (18), 2941-6CODEN: TETRAB; ISSN:0040-4020.The stereochem. is reported for 4 degrdn. products of the title compd. (I).(b) Lin, A. J.; Klayman, D. L.; Hoch, J. M.; Silverton, J. M.; George, C. F. Thermal rearrangement and decomposition products of artemisinin (qinghaosu). J. Org. Chem. 1985, 50, 4504– 4508, DOI: 10.1021/jo00223a017[ACS Full Text], [CAS], Google Scholar165bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL2MXlvFKhurw%253D&md5=98be39207f029e2ef2c431beb61b6b86Thermal rearrangement and decomposition products of artemisinin (qinghaosu)Lin, Ai Jeng; Klayman, Daniel L.; Hoch, James M.; Silverton, James V.; George, Clifford F.Journal of Organic Chemistry (1985), 50 (23), 4504-8CODEN: JOCEAH; ISSN:0022-3263.Thermal rearrangement and decompn. of artermisinin I on a silicone-oil bath preheated to 190° gave three major products II, III, and IV, whose structures were confirmed by x-ray anal.
- 166(a) Gomes, G.; Vil, V.; Terent’ev, A.; Alabugin, I. V. Stereoelectronic source of the anomalous stability of bis-peroxides. Chem. Sci. 2015, 6, 6783– 6791, DOI: 10.1039/C5SC02402A[Crossref], [PubMed], [CAS], Google Scholar.166ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVGisr3O&md5=e2a3658b0ed106108083b72ea1ece7efStereoelectronic source of the anomalous stability of bis-peroxidesGomes, Gabriel dos Passos; Vil', Vera; Terent'ev, Alexander; Alabugin, Igor V.Chemical Science (2015), 6 (12), 6783-6791CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)The unusual stability of bis- and tris-peroxides contradicts the conventional wisdom - some of them can melt without decompn. at temps. exceeding 100 °C. In this work, we disclose a stabilizing stereoelectronic effect that two peroxide groups can exert on each other. This stabilization originates from strong anomeric nO → σ*CO interactions that are absent in mono-peroxides but reintroduced in mols. where two peroxide moieties are sepd. by a CH2 group. Furthermore, such effects can be induced by other σ-acceptors and amplified by structural constraints imposed by cyclic and bicyclic frameworks.(b) Edwards, J. O.; Pearson, R. G. The factors determining nucleophilic reactivities. J. Am. Chem. Soc. 1962, 84, 16– 24, DOI: 10.1021/ja00860a005[ACS Full Text.], [CAS], Google Scholar166bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF38XktlGrsbk%253D&md5=9380eb168691c157e8c03ab5119fcf41The factors determining nucleophilic reactivitiesEdwards, John O.; Pearson, Ralph G.Journal of the American Chemical Society (1962), 84 (1), 16-24CODEN: JACSAT; ISSN:0002-7863.The important factors influencing the reactivity of nucleophilie reagents in the general bimol. nucleophilic substitution reaction N + SX → NS + X are the basicity of N, polarizability of N, and the presence of unshared electron pairs on an atom adjacent to N (called here the α-effect). Basicity becomes an increasingly important factor in the rate of substitution as the pos. charge on S increases; polarizability is most effective when S is electroneg. and has many outer electrons; the α-effect is general for all substrates, SX. Rates of substitution of many nucleophiles on several substrates are tabulated and discussed. Basicity is the most important factor for substitution on carbonyl C, tetrahedral P, trigonal and tetrahedral B, tetrahedral S, and tetrahedral Cl; polarizability is a more important factor when S is Pt(II), HOO-, satd. C, covalent F, trivalent N; aromatic C and S(II) require both factors. The most polarizable reagents examd. were SC(NH2)2, I-, SO3--, S2O3--. The name biphilic agent is suggested for a polarizable nucleophile which donates electrons to S in a a bond and accepts electrons from S in a τ bond; examples are CO and trialkylphosphines.(c) Hoz, S.; Buncel, E. The α-effect: a critical examination of the phenomenon and its origin. Isr. J. Chem. 1985, 26, 313– 319, DOI: 10.1002/ijch.198500113[Crossref], [CAS], Google Scholar.166chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL28XlsFahtrg%253D&md5=11462fce7d52b0823e8c213b7535bd36The α-effect: a critical examination of the phenomenon and its originHoz, S.; Buncel, E.Israel Journal of Chemistry (1985), 26 (4), 313-19CODEN: ISJCAT; ISSN:0021-2148.A few aspects related to the nature and origin of the α-effect are reviewed with 54 refs.(d) Buncel, E.; Um, I. The α-effect and its modulation by solvent. Tetrahedron 2004, 60, 7801– 7825, DOI: 10.1016/j.tet.2004.05.006[Crossref], [CAS], Google Scholar166dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXmsVajtr4%253D&md5=519fbc0a9a68330c7b012922747db85eThe α-effect and its modulation by solventBuncel, Erwin; Um, Ik-HwanTetrahedron (2004), 60 (36), 7801-7825CODEN: TETRAB; ISSN:0040-4020. (Elsevier B.V.)A review. Although several reviews on the α-effect have been published previously, the effect of solvent on the α-effect has been neglected, probably due to a lack of relevant data on solvent effects at that time. The present review will mainly deal with the effect of solvent on the α-effect for various types of reactions, though factors influencing the magnitude of the α-effect will also be discussed.
- 167Haynes, R. K.; Krishna, S. Artemisinins: activities and actions. Microbes Infect. 2004, 6, 1339– 1346, DOI: 10.1016/j.micinf.2004.09.002[Crossref], [PubMed], [CAS], Google Scholar167https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhtVWitLzK&md5=b013c81ce6253e2f77e3a5cd1443c3a3Artemisinins: activities and actionsHaynes, Richard K.; Krishna, SanjeevMicrobes and Infection (2004), 6 (14), 1339-1346CODEN: MCINFS; ISSN:1286-4579. (Elsevier B.V.)A review. Multidrug-resistant malaria caused by Plasmodium falciparum has severely limited treatment options over recent years. Artemisinins are still effective for treating uncomplicated as well as severe malaria, because resistance is not yet clin. apparent. This article reviews some clin. useful properties of artemisinins and how they might work.
- 168(a) O’Neill, P. M.; Barton, V. E.; Ward, S. A. The molecular mechanism of action of artemisinin - the debate continues. Molecules 2010, 15, 1705– 1721, DOI: 10.3390/molecules15031705[Crossref], [PubMed], [CAS], Google Scholar.168ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXjs1ygurY%253D&md5=be4d50f93ea4c66578d5043f164dab31The molecular mechanism of action of artemisinin - the debate continuesO'Neill, Paul M.; Barton, Victoria E.; Ward, Stephen A.Molecules (2010), 15 (), 1705-1721CODEN: MOLEFW; ISSN:1420-3049. (Molecular Diversity Preservation International)A review. Despite international efforts to 'roll back malaria' the 2008 World Malaria Report revealed the disease still affects approx. 3 billion people in 109 countries; 45 within the WHO African region. The latest report however does provide some 'cautious optimism'; more than one-third of malarious countries have documented >50% redns. in malaria cases in 2008 compared to 2000. The goal of the Member States at the World Health Assembly and 'Roll Back Malaria' (RBM) partnership is to reduce the nos. of malaria cases and deaths recorded in 2000 by 50% or more by the end of 2010. Although malaria is preventable it is most prevalent in poorer countries where prevention is difficult and prophylaxis is generally not an option. The burden of disease has increased by the emergence of multi drug resistant (MDR) parasites which threatens the use of established and cost effective antimalarial agents. After a major change in treatment policies, artemisinins are now the frontline treatment to aid rapid clearance of parasitemia and quick resoln. of symptoms. Since artemisinin and its derivs. are eliminated rapidly, artemisinin combination therapies (ACT's) are now recommended to delay resistance mechanisms. In spite of these precautionary measures reduced susceptibility of parasites to the artemisinin-based component of ACT's has developed at the Thai-Cambodian border, a historical 'hot spot' for MDR parasite evolution and emergence. This development raises serious concerns for the future of the artemisinins and this is not helped by controversy related to the mode of action. Although a no. of potential targets were proposed the actual mechanism of action remains ambiguous. Interestingly, artemisinins have also shown potent and broad anticancer properties in cell lines and animal models and are becoming established as anti-schistosomal agents. In this review we will discuss the recent evidence explaining bioactivation and potential mol. targets in the chemotherapy of malaria and cancer.(b) Li, Z.; Li, Q.; Wu, J.; Wang, M.; Yu, J. Artemisinin and its derivatives as a repurposing anticancer agent: what else do we need to do?. Molecules 2016, 21, 1331, DOI: 10.3390/molecules21101331[Crossref], [CAS], Google Scholar.168bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhvFaksrvF&md5=e3edbb58fac695ecec98fc970448db96Artemisinin and its derivatives as a repurposing anticancer agent: what else do we need to do?Li, Zhe; Li, Qin; Wu, Jun; Wang, Manyuan; Yu, JunxianMolecules (2016), 21 (10), 1331/1-1331/14CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)Preclin. investigation and clin. experience have provided evidence on the potential anticancer effect of artemisinin and its derivs. (ARTs) in the recent two decades. The major mechanisms of action of ARTs may be due to toxic-free radicals generated by an endoperoxide moiety, cell cycle arrest, induction of apoptosis, and inhibition of tumor angiogenesis. It is very promising that ARTs are expected to be a new class of antitumor drugs of wide spectrum due to their detailed information regarding efficacy and safety. For developing repurposed drugs, many other characteristics of ARTs should be studied, including through further investigations on possible new pathways of anticancer effects, exploration on efficient and specific drug delivery systems-esp. crossing biol. barriers, and obtaining sufficient data in clin. trials. The aim of this review is to highlight these achievements and propose the potential strategies to develop ARTs as a new class of cancer therapeutic agents.(c) Cui, L.; Su, X. Z. Discovery, mechanisms of action and combination therapy of artemisinin. Expert Rev. Anti-Infect. Ther. 2009, 7, 999– 1013, DOI: 10.1586/eri.09.68[Crossref], [PubMed], [CAS], Google Scholar.168chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXht1Wru7fM&md5=29fb8392d6b533f4073e958eab1fe1f9Discovery, mechanisms of action and combination therapy of artemisininCui, Li-Wang; Su, Xin-ZhuanExpert Review of Anti-Infective Therapy (2009), 7 (8), 999-1013CODEN: ERATCK; ISSN:1478-7210. (Expert Reviews Ltd.)A review. Despite great international efforts, malaria still inflicts an enormous toll on human lives, esp. in Africa. Throughout history, antimalarial medicines have been one of the most powerful tools in malaria control. However, the acquisition and spread of parasite strains that are resistant to multiple antimalarial drugs have become one of the greatest challenges to malaria treatment, and are assocd. with the increase in morbidity and mortality in many malaria-endemic countries. To deal with this grave situation, artemisinin-based combinatory therapies (ACTs) have been introduced and widely deployed in malarious regions. Artemisinin is a new class of antimalarial compds. discovered by Chinese scientists from the sweet wormwood Artemisia annua. The potential development of resistance to artemisinins by Plasmodium falciparum threatens the usable lifespan of ACTs, and therefore is a subject of close surveillance and extensive research. Studies at the Thai-Cambodian border, a historical epicenter of multidrug resistance, have detected reduced susceptibility to artemisinins as manifested by prolonged parasite-clearance times, raising considerable concerns on resistance development. Despite this significance, there is still controversy on the mode of action of artemisinins. Although a no. of potential cellular targets of artemisinins have been proposed, they remain to be verified exptl. Here, we review the history of artemisinin discovery, discuss the mode of action and potential drug targets, and present strategies to elucidate resistance mechanisms.(d) Wang, J.; Zhang, C. J.; Chia, W.; Loh, C.; Li, Z.; Lee, Y. M.; He, Y.; Yuan, L. X.; Lim, T. K.; Liu, M.; Liew, C. X.; Lee, Y. Q.; Zhang, J.; Lu, N.; Lim, C. T.; Hua, Z. C.; Liu, B.; Shen, H. M.; Tan, K. S.; Lin, Q. Haem-activated promiscuous targeting of artemisinin in Plasmodium falciparum. Nat. Commun. 2015, 6, 10111, DOI: 10.1038/ncomms10111[Crossref], [PubMed], [CAS], Google Scholar168dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXitVynsLjO&md5=a532a76cdd2f33b0ca23e733e6247a0cHaem-activated promiscuous targeting of artemisinin in Plasmodium falciparumWang, Jigang; Zhang, Chong-Jing; Chia, Wan Ni; Loh, Cheryl C. Y.; Li, Zhengjun; Lee, Yew Mun; He, Yingke; Yuan, Li-Xia; Lim, Teck Kwang; Liu, Min; Liew, Chin Xia; Lee, Yan Quan; Zhang, Jianbin; Lu, Nianci; Lim, Chwee Teck; Hua, Zi-Chun; Liu, Bin; Shen, Han-Ming; Tan, Kevin S. W.; Lin, QingsongNature Communications (2015), 6 (), 10111CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)The mechanism of action of artemisinin and its derivs., the most potent of the anti-malarial drugs, is not completely understood. Here we present an unbiased chem. proteomics anal. to directly explore this mechanism in Plasmodium falciparum. We use an alkyne-tagged artemisinin analog coupled with biotin to identify 124 artemisinin covalent binding protein targets, many of which are involved in the essential biol. processes of the parasite. Such a broad targeting spectrum disrupts the biochem. landscape of the parasite and causes its death. Furthermore, using alkyne-tagged artemisinin coupled with a fluorescent dye to monitor protein binding, we show that haem, rather than free ferrous iron, is predominantly responsible for artemisinin activation. The haem derives primarily from the parasite's haem biosynthesis pathway at the early ring stage and from Hb digestion at the latter stages. Our results support a unifying model to explain the action and specificity of artemisinin in parasite killing.
- 169(a) Lin, A. J.; Klayman, D. L.; Milhous, W. K. Antimalarial activity of new water-soluble dihydroartemisinin derivatives. J. Med. Chem. 1987, 30, 2147– 2150, DOI: 10.1021/jm00394a037[ACS Full Text.], [CAS], Google Scholar169ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL2sXls1yhtr8%253D&md5=0de274333c579fc93e5797fb08adefb9Antimalarial activity of new water-soluble dihydroartemisinin derivativesLin, Ai Jeng; Klayman, Daniel L.; Milhous, Wilbur K.Journal of Medicinal Chemistry (1987), 30 (11), 2147-50CODEN: JMCMAR; ISSN:0022-2623.The title derivs. were prepd. in good yield by treatment of dihydroartemisinin with an appropriate alc. under BF3 etherate catalysis at room temp. All major condensation products were the β isomer. Hydrolysis of the esters with 2.5% KOH/MeOH gave the corresponding K salts, which were converted to free acids (I; R = CO2H or 4-C6H4CO2H and n = 1-3) by acidification. The derivs. were tested in vitro against two clones of human malaria, Plasmodium falciparum D-6 (Sierra Leone clone) and W-2 (Indochina clone). No cross-resistance to the antimalarial agents mefloquine, chloroquine, pyrimethamine, sulfadoxine, and quinine was obsd. In general, the new compds. are more effective against the W-2 than the D-6 strain. Various I esters possessed activity comparable to that of the parent compds. artemisinin and dihydroartemisinin; however, conversion of the esters to their corresponding carboxylates or acids with the exception of artelinic acid (I; R = 4-C6H4CO2H and n = 1), drastically decreased the antimalarial activities in both cell lines. Artelinic acid, which is both water sol. and stable in 2.5% K2CO3 soln., possessed superior in vivo activity against P. berghei than artemisinin or artesunic acid.(b) Lin, A. J.; Zikry, A. B.; Kyle, D. E. Antimalarial activity of new dihydroartemisinin derivatives. 7. 4-(p-Substituted phenyl)-4(R or S)-[10(δ. or β)-dihydroartemisininoxy]butyric acids. J. Med. Chem. 1997, 40, 1396– 1400, DOI: 10.1021/jm9607919[ACS Full Text], [CAS], Google Scholar169bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXitlWjsLo%253D&md5=9271fa56f9a40e9a6e6866907f3e2a64Antimalarial Activity of New Dihydroartemisinin Derivatives. 7. 4-(p-Substituted phenyl)-4(R or S)-[10(α or β)-dihydroartemisininoxy]butyric AcidsLin, Ai J.; Zikry, Akram B.; Kyle, Dennis E.Journal of Medicinal Chemistry (1997), 40 (9), 1396-1400CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)To search for water sol. dihydroartemisinin derivs. with higher efficacy and longer plasma half-life than artesunic or artelinic acid, a series of new stereoisomers of 4-(p-substituted phenyl)-4(R or S)-[10(α or β)-dihydroartemisininoxy]butyric acids were synthesized as new potential antimalarial agents. Two approaches were taken in the design of these new mols. to (a) increase the lipophilicity of the mol. and (b) decrease the rate of oxidative dealkylation of the target compds. The new compds. showed a 2-10-fold increase in in vitro antimalarial activity against D-6 and W-2 clones of Plasmodium falciparum than artemisinin or artelinic acid. R-diastereomers are, in general, more potent than the corresponding S-diastereomers. P-Chlorophenyl and p-bromophenyl derivs. showed in vivo oral antimalarial activity against P. berghei (with 3/8 cured) superior to that of artelinic acid (1/8 cured), whereas p-fluorophenyl and p-methoxyphenyl analogs demonstrated activity only comparable (1/8 cured) to that of artelinic acid at the same dosage level (64 mg/kg twice a day). The in vivo antimalarial activity of these new compds. correlates with their SD50 (50% parasitemia suppression dose). The biol. results suggested that an electronic effect, besides the lipophilicity, may play a role in detg. the efficacy of this class of compds.
- 170Jung, M.; Lee, S. Stability of acetal and non acetal-type analogues of artemisinin in simulated stomach acid. Bioorg. Med. Chem. Lett. 1998, 8, 1003– 1006, DOI: 10.1016/S0960-894X(98)00160-7[Crossref], [PubMed], [CAS], Google Scholar170https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXjtlSntL4%253D&md5=711a622e9d4a075defeb6f27fe7fe71bStability of acetal and non acetal-type analogs of artemisinin in simulated stomach acidJung, Mankil; Lee, SeokjoonBioorganic & Medicinal Chemistry Letters (1998), 8 (9), 1003-1006CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)A series of non acetal-type analogs of artemisinin contg. C-C bond at position-12 have been found to be 15 - 22 times more stable than acetal(C-O)-type prodrugs of artemisinin in simulated stomach acid.
- 171Jung, M.; Lee, K.; Kendrick, H.; Robinson, B. L.; Croft, S. L. Synthesis, stability, and antimalarial activity of new hydrolytically stable and water-soluble (+)-deoxoartelinic acid. J. Med. Chem. 2002, 45, 4940– 4944, DOI: 10.1021/jm020244p[ACS Full Text], [CAS], Google Scholar171https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XmvVShsLs%253D&md5=b302136bb6adc609ea0f7dd91685fd84Synthesis, Stability, and Antimalarial Activity of New Hydrolytically Stable and Water-Soluble (+)-Deoxoartelinic AcidJung, Mankil; Lee, Kyunghoon; Kendrick, Howard; Robinson, Brian L.; Croft, Simon L.Journal of Medicinal Chemistry (2002), 45 (22), 4940-4944CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)(+)-Deoxoartelinic acid (I), a new hydrolytically stable, water-sol., and potent non-acetal-type antimalarial drug candidate, was successfully prepd. from artemisinic acid by using sulfur ylide and photooxygenative cyclization in seven steps. I showed superior in vitro antimalarial activity against the chloroquine-resistant K1 strain of Plasmodium falciparum and higher suppression (98.7%) than arteether in vivo against Plasmodium chabaudi infected mice. I also showed remarkable stability with a half-life of 258.66 h, 23 times more stable than clin. useful arteether in simulated stomach acid, and improved soly., 4 times more sol. than artemisinin in water.
- 172Singh, C.; Verma, V. P.; Hassam, M.; Singh, A. S.; Naikade, N. K.; Puri, S. K. New orally active amino- and hydroxy-functionalized 11-azaartemisinins and their derivatives with high order of antimalarial activity against multidrug-resistant Plasmodium yoelii in Swiss mice. J. Med. Chem. 2014, 57, 2489– 2497, DOI: 10.1021/jm401774f[ACS Full Text], [CAS], Google Scholar172https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXisFKhs7k%253D&md5=e4518e78d108f4e688956f7afdd30357New Orally Active Amino- and Hydroxy-Functionalized 11-Azaartemisinins and Their Derivatives with High Order of Antimalarial Activity against Multidrug-Resistant Plasmodium yoelii in Swiss MiceSingh, Chandan; Verma, Ved Prakash; Hassam, Mohammad; Singh, Ajit Shankar; Naikade, Niraj K.; Puri, Sunil K.Journal of Medicinal Chemistry (2014), 57 (6), 2489-2497CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)By use of artemisinin as the starting material, two new amino- and hydroxy-functionalized 11-azaartemisinins and their derivs. have been prepd. and screened for antimalarial activity by oral route against multidrug-resistant Plasmodium yoelii in Swiss mice. While N-amino- and N-hydroxy- 11-azaartemisinin showed only modest activity, several of their derivs. showed high order of antimalarial activity. Biphenyl-based compd. I, the most active compd. of the series, provided 100% and 80% protection to the infected mice at 12 mg/kg × 4 days and 6 mg/kg × 4 days, resp. Some compds. showed 100% protection at 12 mg/kg × 4 days, while other compds. showed similar levels of protection at 24 mg/kg × 4 days. Clin. useful drug β-arteether provided 100% protection at 48 mg/kg × 4 days and 20% protection at 24 mg/kg × 4 days in this model.
- 173Haynes, R. K.; Fugmann, B.; Stetter, J.; Rieckmann, K.; Heilmann, H.; Chan, H.; Cheung, M.; Lam, W.; Wong, H.; Croft, S. L.; Vivas, L.; Rattray, L.; Stewart, L.; Peters, W.; Robinson, B. L.; Edstein, M. D.; Kotecka, B.; Kyle, D. E.; Beckermann, B.; Gerisch, M.; Radtke, M.; Schmuck, G.; Steinke, W.; Wollborn, U.; Schmeer, K.; Romer, A. Artemisone - a highly active antimalarial drug of the artemisinin class. Angew. Chem., Int. Ed. 2006, 45, 2082– 2088, DOI: 10.1002/anie.200503071[Crossref], [CAS], Google Scholar173https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xjt1Ogs7s%253D&md5=00e60d8f412ecadc851db62a87e4a9c9Artemisone - a highly active antimalarial drug of the artemisinin classHaynes, Richard K.; Fugmann, Burkhard; Stetter, Jorg; Rieckmann, Karl; Heilmann, Hans-Dietrich; Chan, Ho-Wai; Cheung, Man-Ki; Lam, Wai-Lun; Wong, Ho-Ning; Croft, Simon L.; Vivas, Livia; Rattray, Lauren; Stewart, Lindsay; Peters, Wallace; Robinson, Brian L.; Edstein, Michael D.; Kotecka, Barbara; Kyle, Dennis E.; Beckermann, Bernhard; Gerisch, Michael; Radtke, Martin; Schmuck, Gabriele; Steinke, Wolfram; Wollborn, Ute; Schmeer, Karl; Romer, AxelAngewandte Chemie, International Edition (2006), 45 (13), 2082-2088CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)Efficacies of artemisone (I) against malaria parasites are substantially greater than those of the current artemisinin "gold std.", artesunate. In contrast to most current artemisinins, I displays low lipophilicity and negligible neuro- and cytotoxicity in in vitro and in vivo assays. Thus, the drug offers promise for use in artemisinin-based combination therapy.
- 174Wang, X.; Dong, Y.; Wittlin, S.; Charman, S. A.; Chiu, F. C.; Chollet, J.; Katneni, K.; Mannila, J.; Morizzi, J.; Ryan, E.; Scheurer, C.; Steuten, J.; Tomas, J. S.; Snyder, C.; Vennerstrom, J. L. Comparative antimalarial activities and ADME profiles of ozonides (1,2,4-trioxolanes) OZ277, OZ439, and their 1,2-dioxolane, 1,2,4-trioxane, and 1,2,4,5-tetraoxane isosteres. J. Med. Chem. 2013, 56, 2547– 2555, DOI: 10.1021/jm400004u[ACS Full Text], [CAS], Google Scholar174https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXktVCksb0%253D&md5=ebba930db3a19ccb90bc8feb57389972Comparative Antimalarial Activities and ADME Profiles of Ozonides (1,2,4-trioxolanes) OZ277, OZ439, and Their 1,2-Dioxolane, 1,2,4-Trioxane, and 1,2,4,5-Tetraoxane IsosteresWang, Xiaofang; Dong, Yuxiang; Wittlin, Sergio; Charman, Susan A.; Chiu, Francis C. K.; Chollet, Jacques; Katneni, Kasiram; Mannila, Janne; Morizzi, Julia; Ryan, Eileen; Scheurer, Christian; Steuten, Jessica; Santo Tomas, Josefina; Snyder, Christopher; Vennerstrom, Jonathan L.Journal of Medicinal Chemistry (2013), 56 (6), 2547-2555CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)To ascertain the structure-activity relationship of the core 1,2,4-trioxolane substructure of dispiro ozonides OZ277 and OZ439, we compared the antimalarial activities and ADME profiles of the 1,2-dioxolane, 1,2,4-trioxane, and 1,2,4,5-tetraoxane isosteres. Consistent with previous data, both dioxolanes had very weak antimalarial properties. For the OZ277 series, the trioxane isostere had the best ADME profile, but its overall antimalarial efficacy was not superior to that of the trioxolane or tetraoxane isosteres. For the OZ439 series, there was a good correlation between the antimalarial efficacy and ADME profiles in the rank order trioxolane > trioxane > tetraoxane. As we have previously obsd. for OZ439 vs. OZ277, the OZ439 series peroxides had superior exposure and efficacy in mice compared to the corresponding OZ277 series peroxides.
- 175(a) Benoit-Vical, F.; Lelievre, J.; Berry, A.; Deymier, C.; Dechy-Cabaret, O.; Cazelles, J.; Loup, C.; Robert, A.; Magnaval, J.; Meunier, B. Trioxaquines are new antimalarial agents active on all erythrocytic forms, including gametocytes. Antimicrob. Agents Chemother. 2007, 51, 1463– 1472, DOI: 10.1128/AAC.00967-06[Crossref], [PubMed], [CAS], Google Scholar.175ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXktlOjtbg%253D&md5=a9ed6a6d13c3cb9e6e7991ef02daf578Trioxaquines are new antimalarial agents active on all erythrocytic forms, including gametocytesBenoit-Vical, Francoise; Lelievre, Joel; Berry, Antoine; Deymier, Caroline; Dechy-Cabaret, Odile; Cazelles, Jerome; Loup, Christophe; Robert, Anne; Magnaval, Jean-Francois; Meunier, BernardAntimicrobial Agents and Chemotherapy (2007), 51 (4), 1463-1472CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)Malaria is the third most significant cause of infectious disease in the world. The search for new antimalarial chemotherapy has become increasingly urgent due to parasite resistance to classical drugs. Trioxaquines are synthetic hybrid mols. contg. a trioxane motif (which is responsible for the antimalarial activity of artemisinin) linked to an aminoquinoline entity (which is responsible for the antiplasmodial properties of chloroquine). These trioxaquines are highly potent against young erythrocytic stages of Plasmodium falciparum and exhibit efficient activity in vitro against chloroquine-sensitive and -resistant strains of P. falciparum (50% inhibitory concn., 4 to 32 nM) and are also active in vivo against P. vinckei petteri and P. yoelii nigeriensis in suppressive and curative murine tests. The trioxaquine DU1302 is one of these promising antimalarial agents. The present study confirms the absence of toxicity of this drug on cell lines and in a mice model. Moreover, DU1302 exhibits potent activity against gametocytes, the form transmitted by mosquitoes, as killing of the gametocytes is essential to limit the spread of malaria. The ease of chem. synthesis of this trioxaquine prototype should be considered an addnl. advantage and would make these drugs affordable without perturbations of the drug supply.(b) Cosledan, F.; Fraisse, L.; Pellet, A.; Guillou, F.; Mordmuller, B.; Kremsner, P. G.; Moreno, A.; Mazier, D.; Maffrand, J.-P.; Meunier, B. Selection of a trioxaquine as an antimalarial drug candidate. Proc. Natl. Acad. Sci. U. S. A. 2008, 105, 17579– 17584, DOI: 10.1073/pnas.0804338105[Crossref], [PubMed], [CAS], Google Scholar.175bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsVWntbnP&md5=779ad725de8eb3f7fb528fd5aa0e71fdSelection of a trioxaquine as an antimalarial drug candidateCosledan, Frederic; Fraisse, Laurent; Pellet, Alain; Guillou, Francois; Mordmueller, Benjamin; Kremsner, Peter G.; Moreno, Alicia; Mazier, Dominique; Maffrand, Jean-Pierre; Meunier, BernardProceedings of the National Academy of Sciences of the United States of America (2008), 105 (45), 17579-17584CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Trioxaquines are antimalarial agents based on hybrid structures with a dual mode of action. One of these mols., PA1103/SAR116242, is highly active in vitro on several sensitive and resistant strains of Plasmodium falciparum at nanomolar concns. (e.g., IC50 value = 10 nM with FcM29, a chloroquine-resistant strain) and also on multidrug-resistant strains obtained from fresh patient isolates in Gabon. This mol. is very efficient by oral route with a complete cure of mice infected with chloroquine-sensitive or chloroquine-resistant strains of Plasmodia at 26-32 mg/kg. This compd. is also highly effective in humanized mice infected with P. falciparum. Combined with a good drug profile (preliminary absorption, metab., and safety parameters), these data were favorable for the selection of this particular trioxaquine for development as drug candidate among 120 other active hybrid mols.(c) Waseem, Y.; Hasan, C. A.; Ahmed, F. Artemisinin: A promising adjunct for cancer therapy. Cureus. 2018, 10 (11), e3628 DOI: 10.7759/cureus.3628 .(d) Fröhlich, T.; Çapcı, K. A.; Reiter, C.; Tsogoeva, S. B. Artemisinin-derived dimers: potent antimalarial and anticancer agents. J. Med. Chem. 2016, 59 (16), 7360– 88, DOI: 10.1021/acs.jmedchem.5b01380[ACS Full Text.], [CAS], Google Scholar175dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC28fjtlKhsA%253D%253D&md5=0bc32b707e395961bf4a61a2c0665061Artemisinin-Derived Dimers: Potent Antimalarial and Anticancer AgentsFrohlich Tony; Capci Karagoz Aysun; Reiter Christoph; Tsogoeva Svetlana BJournal of medicinal chemistry (2016), 59 (16), 7360-88 ISSN:.The development of new efficient therapeutics for the treatment of malaria and cancer is an important endeavor. Over the past 15 years, much attention has been paid to the synthesis of dimeric structures, which combine two units of artemisinin, as lead compounds of interest. A wide variety of atemisinin-derived dimers containing different linkers demonstrate improved properties compared to their parent compounds (e.g., circumventing multidrug resistance), making the dimerization concept highly compelling for development of efficient antimalarial and anticancer drugs. The present Perspective highlights recent developments on different types of artemisinin-derived dimers and their structural and functional features. Particular emphasis is put on the respective in vitro and in vivo studies, exploring the role of the length and nature of linkers on the activities of the dimers, and considering the future prospects of the dimerization concept for drug discovery.(e) Singh, N. P.; Lai, H. C.; Park, J. S.; Gerhardt, T. E.; Kim, B. J.; Wang, S.; Sasaki, T. Effects of artemisinin dimers on rat breast cancer cells in vitro and in vivo. Anticancer Res. 2011, 31 (12), 4111– 4[PubMed], [CAS], Google Scholar.175ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsFCmurk%253D&md5=70fcb4c00d0a68578d167f666db5e7a0Effects of artemisinin dimers on rat breast cancer cells in vitro and in vivoSingh, Narendra P.; Lai, Henry C.; Park, Ji Sun; Gerhardt, Thomas E.; Kim, Byung Ju; Wang, Shusheng; Sasaki, TomikazuAnticancer Research (2011), 31 (12), 4111-4114CODEN: ANTRD4; ISSN:0250-7005. (International Institute of Anticancer Research)Artemisinin has been shown to be an effective antimalarial and anticancer compd. Dimers of artemisinin have been synthesized and shown to be potent antimalarials compared with monomers. In the present study, we investigated the effect of two artemisinin dimers (dimer-alc. and dimer-hydrazone) on rat mammary adeno-carcinoma cells (MTLn3) in vitro and in vivo compared with that of the artemisinin monomer dihydroartemisinin (DHA). We found that the dimers are considerably more potent than DHA in killing MTLn3 cells in vitro and suppressing the growth of MTLn3 breast tumors in vivo.(f) Moses, B. S.; McCullough, S.; Fox, J. M.; Mott, B. T.; Bentzen, S. M.; Kim, M.; Tyner, J. W.; Lapidus, R. G.; Emadi, A.; Rudek, M. A.; Kingsbury, T. J.; Civin, C. Antileukemic efficacy of a potent artemisinin combined with sorafenib and venetoclax. Blood Adv. 2021, 5 (3), 711– 724, DOI: 10.1182/bloodadvances.2020003429[Crossref], [PubMed], [CAS], Google Scholar.175fhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXnt1Sns7g%253D&md5=9d2906d8b1038d22d4537803e3151188Antileukemic efficacy of a potent artemisinin combined with sorafenib and venetoclaxMoses, Blake S.; McCullough, Samantha; Fox, Jennifer M.; Mott, Bryan T.; Bentzen, Soeren M.; Kim, MinJung; Tyner, Jeffrey W.; Lapidus, Rena G.; Emadi, Ashkan; Rudek, Michelle A.; Kingsbury, Tami J.; Civin, Curt I.Blood Advances (2021), 5 (3), 711-724CODEN: BALDBA; ISSN:2473-9537. (American Society of Hematology)Artemisinins are active against human leukemia cell lines and have low clin. toxicity in worldwide use as antimalarials. Because multiagent combination regimens are necessary to cure fully evolved leukemias, we sought to leverage our previous finding that artemisinin analogs synergize with kinase inhibitors, including sorafenib (SOR), by identifying addnl. synergistic antileukemic drugs with low toxicity. An oral 3-drug "SAV" regimen (SOR plus the potent artemisinin-derived trioxane diphenylphosphate 838 dimeric analog [ART838] plus VEN) killed leukemia cell lines and primary cells in vitro. Leukemia cells cultured in ART838 had decreased induced myeloid leukemia cell differentiation protein (MCL1) levels and increased levels of DNA damage-inducible transcript 3 (DDIT3; GADD153) mRNA and its encoded CCATT/enhancer-binding protein homologous protein (CHOP), a key component of the integrated stress response. Thus, synergy of the SAV combination may involve combined targeting of MCL1 and BCL2 via discrete, tolerable mechanisms, and cellular levels of MCL1 and DDIT3/CHOP may serve as biomarkers for action of artemisinins and SAV. Finally, SAV treatment was tolerable and resulted in deep responses with extended survival in 2 acute myeloid leukemia (AML) cell line xenograft models, both harboring a mixed lineage leukemia gene rearrangement and an FMS-like receptor tyrosine kinase-3 internal tandem duplication, and inhibited growth in 2 AML primagraft models.(g) Cheng, C.; Wang, T.; Song, Z.; Peng, L.; Gao, M.; Hermine, O.; Rousseaux, S.; Khochbin, S.; Mi, J. Q.; Wang, J. Induction of autophagy and autophagy-dependent apoptosis in diffuse large B-cell lymphoma by a new antimalarial artemisinin derivative, SM1044. Cancer Med. 2018, 7 (2), 380– 396, DOI: 10.1002/cam4.1276[Crossref], [PubMed], [CAS], Google Scholar175ghttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisVCitro%253D&md5=982b4862179ccc43b5983d6a77a7bb79Induction of autophagy and autophagy-dependent apoptosis in diffuse large B-cell lymphoma by a new antimalarial artemisinin derivative, SM1044Cheng, Chunyan; Wang, Tao; Song, Zhiqun; Peng, Lijun; Gao, Mengqing; Hermine, Olivier; Rousseaux, Sophie; Khochbin, Saadi; Mi, Jian-Qing; Wang, JinCancer Medicine (2018), 7 (2), 380-396CODEN: CMAEDL; ISSN:2045-7634. (John Wiley & Sons Ltd.)Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin's lymphoma. R-CHOP is currently the std. therapy for DLBCL, but the prognosis of refractory or recurrent patients remains poor. In this study, we synthesized a new water-sol. antimalarial drug artemisinin deriv., SM1044. The treatment of DLBCL cell lines with SM1044 induces autophagy-dependent apoptosis, which is directed by an accelerated degrdn. of the antiapoptosis protein Survivin, via its acetylation-dependent interaction with the autophagy-related protein LC3-II. Addnl., SM1044 also stimulates the de novo synthesis of ceramide, which in turn activates the CaMKK2-AMPK-ULK1 axis, leading to the initiation of autophagy. Our findings not only elucidate the mechanism of autophagy-dependent apoptosis in DLBCL cells, but also suggest that SM1044 is a promising therapeutic mol. for the treatment of DLBCL, along with R-CHOP regimen.
- 176(a) Vennerstrom, J. L.; Arbe-Barnes, S.; Brun, R.; Charman, S. A.; Chiu, F. C.; Chollet, J.; Dong, Y.; Dorn, A.; Hunziker, D.; Matile, H.; McIntosh, K.; Padmanilayam, M.; Tomas, J. S.; Scheurer, C.; Scorneaux, B.; Tang, Y.; Urwyler, H.; Wittlin, S.; Charman, W. N. Identification of an antimalarial synthetic trioxolane drugdevelopment candidate. Nature 2004, 430, 900– 904, DOI: 10.1038/nature02779[Crossref], [PubMed], [CAS], Google Scholar.176ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXmslCnurY%253D&md5=71070255d32c12fe3c227d5091225b31Identification of an antimalarial synthetic trioxolane drug development candidateVennerstrom, Jonathan L.; Arbe-Barnes, Sarah; Brun, Reto; Charman, Susan A.; Chiu, Francis C. K.; Chollet, Jacques; Dong, Yuxiang; Dorn, Arnulf; Hunziker, Daniel; Matile, Hugues; McIntosh, Kylie; Padmanilayam, Maniyan; Santo Tomas, Josefina; Scheurer, Christian; Scorneaux, Bernard; Tang, Yuanqing; Urwyler, Heinrich; Wittlin, Sergio; Charman, William N.Nature (London, United Kingdom) (2004), 430 (7002), 900-904CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)The discovery of artemisinin more than 30 yr ago provided a completely new antimalarial structural prototype; i.e., a mol. with a pharmacophoric peroxide bond in a unique 1,2,4-trioxane heterocycle. Available evidence suggests that artemisinin and related peroxidic antimalarial drugs exert their parasiticidal activity subsequent to reductive activation by hem, released as a result of Hb digestion by the malaria-causing parasite. This irreversible redox reaction produces carbon-centered free radicals, leading to alkylation of hem and proteins (enzymes), one of which-the sarcoplasmic-endoplasmic reticulum ATPase PfATP6 (ref. 7)-may be crit. to parasite survival. Notably, there is no evidence of drug resistance to any member of the artemisinin family of drugs. The chemotherapy of malaria has benefited greatly from the semi-synthetic artemisinins artemether and artesunate as they rapidly reduce parasite burden, have good therapeutic indexes and provide for successful treatment outcomes. However, as a drug class, the artemisinins suffer from chem. (semi-synthetic availability, purity and cost), biopharmaceutical (poor bioavailability and limiting pharmacokinetics) and treatment (noncompliance with long treatment regimens and recrudescence) issues that limit their therapeutic potential. Here the authors describe how a synthetic peroxide antimalarial drug development candidate was identified in a collaborative drug discovery project.(b) Dong, Y.; Tang, Y.; Chollet, J.; Matile, H.; Wittlin, S.; Charman, S. A.; Charman, W. N.; Tomas, J. S.; Scheurer, C.; Snyder, C. Effect of functional group polarity on the antimalarial activity of spiro and dispiro-1,2,4-trioxolanes. Bioorg. Med. Chem. 2006, 14, 6368– 6382, DOI: 10.1016/j.bmc.2006.05.041[Crossref], [PubMed], [CAS], Google Scholar.176bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XosVOhsLs%253D&md5=0e8953d3541244648820903c5756a9e8Effect of functional group polarity on the antimalarial activity of spiro and dispiro-1,2,4-trioxolanesDong, Yuxiang; Tang, Yuanqing; Chollet, Jacques; Matile, Hugues; Wittlin, Sergio; Charman, Susan A.; Charman, William N.; Tomas, Josefina Santo; Scheurer, Christian; Snyder, Christopher; Scorneaux, Bernard; Bajpai, Saroj; Alexander, Scott A.; Wang, Xiaofang; Padmanilayam, Maniyan; Cheruku, Srinivasa R.; Brun, Reto; Vennerstrom, Jonathan L.Bioorganic & Medicinal Chemistry (2006), 14 (18), 6368-6382CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)Based on the structures of several lipophilic trioxolane antimalarial prototypes, the authors set out to det. which functional groups were assocd. with good antimalarial profiles and identify more polar (lower Log P/Log D) lead compds. with good physicochem. properties. More lipophilic trioxolanes tended to have better oral activities than their more polar counterparts. Trioxolanes with a wide range of neutral and basic, but not acidic, functional groups had good antimalarial profiles.(c) Kim, H. S.; Hammill, J. T.; Guy, R. K. Seeking the elusive long-acting ozonide: discovery of artefenomel (OZ439). J. Med. Chem. 2017, 60, 2651– 2653, DOI: 10.1021/acs.jmedchem.7b00299[ACS Full Text.], [CAS], Google Scholar176chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXkt1Wktbo%253D&md5=e5c43979aaf0f7b6d0bce53c817cd733Seeking the Elusive Long-Acting Ozonide: Discovery of Artefenomel (OZ439)Kim, Ho Shin; Hammill, Jared T.; Guy, R. KiplinJournal of Medicinal Chemistry (2017), 60 (7), 2651-2653CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The majority of frontline therapies for the treatment of malaria are combination drugs contg. artemisinin (or its semisynthetic analogs), known as artemisinin combination therapies (ACTs). While generally efficacious, ACTs and the first generation fully synthetic ozonide, arterolane (OZ277, 1), suffer from rapid clearance requiring 3-day dosing regimens. Extensive structure-activity studies led to the discovery of a second-generation ozonide, artefenomel (OZ439, 2), which has overcome this limitation, maintaining the rapid onset of action and potent activity of the artemisinin derivs. while exhibiting greatly improved pharmacokinetics, low projected cost of goods, prophylactic activity, and the potential for a single dose cure.(d) Dong, Y.; Wang, X.; Kamaraj, S.; Bulbule, V. J.; Chiu, F. C.; Chollet, J.; Dhanasekaran, M.; Hein, C. D.; Papastogiannidis, P.; Morizzi, J.; Shackleford, D. M.; Barker, H.; Ryan, E.; Scheurer, C.; Tang, Y.; Zhao, Q.; Zhou, L.; White, K. L.; Urwyler, H.; Charman, W. N.; Matile, H.; Wittlin, S.; Charman, S. A.; Vennerstrom, J. L. Structure-activity relationship of the antimalarial ozonide artefenomel (OZ439). J. Med. Chem. 2017, 60, 2654– 2668, DOI: 10.1021/acs.jmedchem.6b01586[ACS Full Text.], [CAS], Google Scholar176dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXkslaitQ%253D%253D&md5=132212a3a83d1065f72151984f7c4c27Structure-Activity Relationship of the Antimalarial Ozonide Artefenomel (OZ439)Dong, Yuxiang; Wang, Xiaofang; Kamaraj, Sriraghavan; Bulbule, Vivek J.; Chiu, Francis C. K.; Chollet, Jacques; Dhanasekaran, Manickam; Hein, Christopher D.; Papastogiannidis, Petros; Morizzi, Julia; Shackleford, David M.; Barker, Helena; Ryan, Eileen; Scheurer, Christian; Tang, Yuanqing; Zhao, Qingjie; Zhou, Lin; White, Karen L.; Urwyler, Heinrich; Charman, William N.; Matile, Hugues; Wittlin, Sergio; Charman, Susan A.; Vennerstrom, Jonathan L.Journal of Medicinal Chemistry (2017), 60 (7), 2654-2668CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Building on insights gained from the discovery of the antimalarial ozonide arterolane (OZ277), we now describe the structure-activity relationship (SAR) of the antimalarial ozonide artefenomel (OZ439). Primary and secondary amino ozonides had higher metabolic stabilities than tertiary amino ozonides, consistent with their higher pKa and lower log D7.4 values. For primary amino ozonides, addn. of polar functional groups decreased in vivo antimalarial efficacy. For secondary amino ozonides, addnl. functional groups had variable effects on metabolic stability and efficacy, but the most effective members of this series also had the highest log D7.4 values. For tertiary amino ozonides, addn. of polar functional groups with H-bond donors increased metabolic stability but decreased in vivo antimalarial efficacy. Primary and tertiary amino ozonides with cycloalkyl and heterocycle substructures were superior to their acyclic counterparts. The high curative efficacy of these ozonides was most often assocd. with high and prolonged plasma exposure, but exposure on its own did not explain the presence or absence of either curative efficacy or in vivo toxicity.(e) Phyo, A. P.; Jittamala, P.; Nosten, F. N.; Pukrittayakamee, S.; Imwong, M.; White, N. J.; Duparc, S.; Macintyre, F.; Baker, M.; Möhrle, J. J. Antimalarial activity of artefenomel (OZ439), a novel synthetic antimalarial endoperoxide, in patients with Plasmodium falciparum and Plasmodium vivax malaria: an open-label phase 2 trial. Lancet Infect. Dis. 2016, 16, 61– 69, DOI: 10.1016/S1473-3099(15)00320-5[Crossref], [PubMed], [CAS], Google Scholar176ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhs1Wjs7vP&md5=368550e5ec73242c603c8abdc6a66f12Antimalarial activity of artefenomel (OZ439), a novel synthetic antimalarial endoperoxide, in patients with Plasmodium falciparum and Plasmodium vivax malaria: an open-label phase 2 trialPhyo, Aung Pyae; Jittamala, Podjanee; Nosten, Francois H.; Pukrittayakamee, Sasithon; Imwong, Mallika; White, Nicholas J.; Duparc, Stephan; MacIntyre, Fiona; Baker, Mark; Mohrle, Jorg J.Lancet Infectious Diseases (2016), 16 (1), 61-69CODEN: LIDABP; ISSN:1473-3099. (Elsevier Ltd.)Artefenomel (OZ439) is a novel synthetic trioxolane with improved pharmacokinetic properties compared with other antimalarial drugs with the artemisinin pharmacophore. Artefenomel has been generally well tolerated in volunteers at doses up to 1600 mg and is being developed as a partner drug in an antimalarial combination treatment. We investigated the efficacy, tolerability, and pharmacokinetics of artefenomel at different doses in patients with Plasmodium falciparum or Plasmodium vivax malaria. This phase 2a exploratory, open-label trial was done at the Hospital for Tropical Diseases, Bangkok, and the Shoklo Malaria Research Unit in Thailand. Adult patients with acute, uncomplicated P falciparum or P vivax malaria received artefenomel in a single oral dose (200 mg, 400 mg, 800 mg, or 1200 mg). The first cohort received 800 mg. Testing of a new dose of artefenomel in a patient cohort was decided on after safety and efficacy assessment of the preceding cohort. The primary endpoint was the natural log parasite redn. per 24 h. Definitive oral treatment was given at 36 h. This trial is registered with ClinicalTrials.gov, no. NCT01213966. Between Oct 24, 2010, and May 25, 2012, 82 patients were enrolled (20 in each of the 200 mg, 400 mg, and 800 mg cohorts, and 21 in the 1200 mg cohort). One patient withdrew consent (before the administration of artefenomel) but there were no further dropouts. The parasite redn. rates per 24 h ranged from 0·90 to 1·88 for P falciparum, and 2·09 to 2·53 for P vivax. All doses were equally effective in both P falciparum and P vivax malaria, with median parasite clearance half-lives of 4·1 h (range 1·3-6·7) to 5·6 h (2·0-8·5) for P falciparum and 2·3 h (1·2-3·9) to 3·2 h (0·9-15·0) for P vivax. Maximum plasma concns., dose-proportional to 800 mg, occurred at 4 h (median). The estd. elimination half-life was 46-62 h. No serious drug-related adverse effects were reported; other adverse effects were generally mild and reversible, with the highest no. in the 1200 mg cohort (17 [81%] patients with at least one adverse event). The most frequently reported adverse effect was an asymptomatic increase in plasma creatine phosphokinase concn. (200 mg, n=5; 400 mg, n=3; 800 mg, n=1; 1200 mg, n=3). Artefenomel is a new synthetic antimalarial peroxide with a good safety profile that clears parasitemia rapidly in both P falciparum and P vivax malaria. Its long half-life suggests a possible use in a single-dose treatment in combination with other drugs. Bill & Melinda Gates Foundation, Wellcome Trust, and UK Department for International Development.
- 177Opsenica, I.; Opsenica, D.; Smith, K. S.; Milhous, W. K.; Solaja, B. A. Chemical stability of the peroxide bond enables diversified synthesis of potent tetraoxane antimalarials. J. Med. Chem. 2008, 51, 2261– 2266, DOI: 10.1021/jm701417a[ACS Full Text], [CAS], Google Scholar177https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXjtFSksL8%253D&md5=1cbaada0a733461053126be47a63256fChemical stability of the peroxide bond enables diversified synthesis of potent tetraoxane antimalarialsOpsenica, Igor; Opsenica, Dejan; Smith, Kirsten S.; Milhous, Wilbur K.; Solaja, Bogdan A.Journal of Medicinal Chemistry (2008), 51 (7), 2261-2266CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Of 17 prepd. 1,2,4,5-tetraoxacyclohexanes stable to reductive and acidic conditions, 3 of them were more active than artemisinin against CQ and MFQ resistant strain TM91C235 and all compds. were more active in vitro against W2 than against D6 strain. In vivo, amines 10 and 11a cured all mice at higher doses with MCD ≤ 37.5 (mg/kg)/day. Triol 13 was exceptionally active against melanoma (LOX IMVI) and ovarian cancer (IGROV1), both with LC50 = 60 nM.
- 178(a) Ellis, G. L.; Amewu, R.; Sabbani, S.; Stocks, P. A.; Shone, A.; Stanford, D.; Gibbons, P.; Davies, J.; Vivas, L.; Charnaud, S.; Bongard, E.; Hall, C.; Rimmer, K.; Lozanom, S.; Jesús, M.; Gargallo, D.; Ward, S. A.; O’Neill, P. M. Two-step synthesis of achiral dispiro-1,2,4,5-tetraoxanes with outstanding antimalarial activity, low toxicity, and high-stability profiles. J. Med. Chem. 2008, 51, 2170– 2177, DOI: 10.1021/jm701435h[ACS Full Text.], [CAS], Google Scholar178ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXjtlOjsL4%253D&md5=3c4b69f56bbf84ca035f4fe62716073eTwo-Step Synthesis of Achiral Dispiro-1,2,4,5-tetraoxanes with Outstanding Antimalarial Activity, Low Toxicity, and High-Stability ProfilesEllis, Gemma L.; Amewu, Richard; Sabbani, Sunil; Stocks, Paul A.; Shone, Alison; Stanford, Deborah; Gibbons, Peter; Davies, Jill; Vivas, Livia; Charnaud, Sarah; Bongard, Emily; Hall, Charlotte; Rimmer, Karen; Lozanom, Sonia; Jesus, Maria; Gargallo, Domingo; Ward, Stephen A.; O'Neill, Paul M.Journal of Medicinal Chemistry (2008), 51 (7), 2170-2177CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Piperidinedispirotetraoxanes such as I (R = Et, cyclopropyl) are prepd. by a rapid, two-step method; the products have potent antimalarial activity both in vitro and in vivo. Sulfonylpiperidinones are prepd. by sulfonylation of 4-piperidinone hydrochloride with sulfonyl chlorides; oxidn. of the sulfonylpiperidinones with hydrogen peroxide in the presence of methyltrioxorhenium followed by cyclocondensation with either 2-adamantanone or cyclododecanone in the presence of fluoroboric acid in ether yields the title piperidinedispirotetraoxanes. The 1,2,4,5-tetraoxanes prepd. are more stable than similar 1,2,4-trioxolanes and are both more stable and more active as antimalarial agents than the corresponding 1,2,4-trioxanes. I (R = Et, cyclopropyl) showed no mutagenicity or cytotoxicity at the doses tested in a variety of cell lines. A fluorescent nitrobenzaoxadiazole-tagged tetraoxane is prepd. as a probe; laser scanning confocal microscopy of red blood cells dosed with the probe indicates that tagged mols. accumulate selectively only in parasite infected erythrocytes and that intraparasitic formation of adducts could be inhibited by co-incubation with the iron chelator desferrioxamine.(b) O’Neill, P. M.; Amewu, R. K.; Nixon, G. L.; El Garah, F. B.; Mungthin, M.; Chadwick, J.; Shone, A. E.; Vivas, L.; Lander, H.; Barton, V.; Muangnoicharoen, S.; Bray, P. G.; Davies, J.; Park, B. K.; Wittlin, S.; Brun, R.; Preschel, M.; Zhang, K.; Ward, S. A. Identification of a 1,2,4,5-tetraoxane antimalarial drug-development candidate (RKA182) with superior properties to the semisynthetic artemisinins. Angew. Chem., Int. Ed. 2010, 49, 5693– 5697, DOI: 10.1002/anie.201001026[Crossref], [CAS], Google Scholar.178bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXps1Cqtr4%253D&md5=fde585d889c5784302401ecead267127Identification of a 1,2,4,5-Tetraoxane Antimalarial Drug-Development Candidate (RKA 182) with Superior Properties to the Semisynthetic ArtemisininsO'Neill, Paul M.; Amewu, Richard K.; Nixon, Gemma L.; El Garah, Fatima Bousejra; Mungthin, Mathirut; Chadwick, James; Shone, Alison E.; Vivas, Livia; Lander, Hollie; Barton, Victoria; Muangnoicharoen, Sant; Bray, Patrick G.; Davies, Jill; Park, B. Kevin; Wittlin, Sergio; Brun, Reto; Preschel, Michael; Zhang, Kesheng; Ward, Stephen A.Angewandte Chemie, International Edition (2010), 49 (33), 5693-5697, S5693/1-S5693/10CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)We have identified the first water-sol. 1,2,4,5-tetraoxane drug candidate [I, RKA 182 (ditosylate)] that has outstanding antimalarial activity, stability, low toxicity and ADME properties (absorption, distribution, metab., and excretion) that overcome most of the problems encountered previously with the synthetic and semisynthetic antimalarial endoperoxide drugs that have progressed into preclin. development. This work firmly establishes the potential of the tetraoxane pharmacophore to provide the next generation of synthetic drugs for deployment in the control and eradication of malaria as a component of combination chemotherapy. The industrial synthesis of I comprises only four steps.(c) Marti, F.; Chadwick, J.; Amewu, R. K.; Burrell-Saward, H.; Srivastava, A.; Ward, S. A.; Sharma, R.; Berry, N.; O’Neill, P. M. Second generation analogues of RKA182: synthetic tetraoxanes with outstanding in vitro and in vivo antimalarial activities. MedChemComm 2011, 2, 661– 665, DOI: 10.1039/c1md00102g[Crossref], [CAS], Google Scholar.178chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXotl2gt7Y%253D&md5=f88d1f64a7f22a070d05c32f4b75fd08Second generation analogues of RKA182: synthetic tetraoxanes with outstanding in vitro and in vivo antimalarial activitiesMarti, Francesc; Chadwick, James; Amewu, Richard K.; Burrell-Saward, Hollie; Srivastava, Abhishek; Ward, Stephen A.; Sharma, Raman; Berry, Neil; O'Neill, Paul M.MedChemComm (2011), 2 (7), 661-665CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)A series of polar dispiro-1,2,4,5-tetraoxanes have been designed and synthesized by parallel synthesis. From this series, endoperoxides with activity as low as 0.2 nM have been obtained and representatives of this group have excellent oral activities in the P. berghei ANKA mouse model of malaria.(d) O’Neill, P. M.; Amewu, R. K.; Charman, S. A.; Sabbani, S.; Gnadig, N. F.; Straimer, J.; Fidock, D. A.; Shore, E. R.; Roberts, N. L.; Wong, M. H.; Hong, W. D.; Pidathala, C.; Riley, C.; Murphy, B.; Aljayyoussi, G.; Gamo, F. J.; Sanz, L.; Rodrigues, J.; Cortes, C. C.; Herreros, E.; Angulo-Barturen, I.; Jimenez-Dıaz, M. B.; Bazaga, S. F.; Martınez-Martınez, M. S.; Campo, B.; Sharma, R.; Ryan, E.; Shackleford, D. M.; Campbell, S.; Smith, D. A.; Wirjanata, G.; Noviyanti, R.; Price, R. N.; Marfurt, J.; Palmer, M. J.; Copple, I. M.; Mercer, A. E.; Ruecker, A.; Delves, M. J.; Sinden, R. E.; Sieg, P.; Davies, J.; Rochford, R.; Kocken, C. H.; Zeeman, A.; Nixon, G. L.; Biagini, G. A.; Ward, S. A. A tetraoxane-based antimalarial drug candidate that overcomes PfK13-C580Y dependent artemisinin resistance. Nat. Commun. 2017, 8, 15159, DOI: 10.1038/ncomms15159[Crossref], [PubMed], [CAS], Google Scholar178dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXot12gsb8%253D&md5=652486b04d3bf715b07ccf76c6226db0A tetraoxane-based antimalarial drug candidate that overcomes PfK13-C580Y dependent artemisinin resistanceO'Neill, Paul M.; Amewu, Richard K.; Charman, Susan A.; Sabbani, Sunil; Gnadig, Nina F.; Straimer, Judith; Fidock, David A.; Shore, Emma R.; Roberts, Natalie L.; Wong, Michael H.-L.; Hong, W. David; Pidathala, Chandrakala; Riley, Chris; Murphy, Ben; Aljayyoussi, Ghaith; Gamo, Francisco Javier; Sanz, Laura; Rodrigues, Janneth; Cortes, Carolina Gonzalez; Herreros, Esperanza; Angulo-Barturen, Inigo; Jimenez-Diaz, Maria Belen; Bazaga, Santiago Ferrer; Martinez-Martinez, Maria Santos; Campo, Brice; Sharma, Raman; Ryan, Eileen; Shackleford, David M.; Campbell, Simon; Smith, Dennis A.; Wirjanata, Grennady; Noviyanti, Rintis; Price, Ric N.; Marfurt, Jutta; Palmer, Michael J.; Copple, Ian M.; Mercer, Amy E.; Ruecker, Andrea; Delves, Michael J.; Sinden, Robert E.; Siegl, Peter; Davies, Jill; Rochford, Rosemary; Kocken, Clemens H. M.; Zeeman, Anne-Marie; Nixon, Gemma L.; Biagini, Giancarlo A.; Ward, Stephen A.Nature Communications (2017), 8 (), 15159CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)K13 gene mutations are a primary marker of artemisinin resistance in Plasmodium falciparum malaria that threatens the long-term clin. utility of artemisinin-based combination therapies, the cornerstone of modern day malaria treatment. Here we describe a multinational drug discovery program that has delivered a synthetic tetraoxane-based mol., E209, which meets key requirements of the Medicines for Malaria Venture drug candidate profiles. E209 has potent nanomolar inhibitory activity against multiple strains of P. falciparum and P. vivax in vitro, is efficacious against P. falciparum in in vivo rodent models, produces parasite redn. ratios equiv. to dihydroartemisinin and has pharmacokinetic and pharmacodynamic characteristics compatible with a single-dose cure. In vitro studies with transgenic parasites expressing variant forms of K13 show no cross-resistance with the C580Y mutation, the primary variant obsd. in Southeast Asia. E209 is a superior next generation endoperoxide with combined pharmacokinetic and pharmacodynamic features that overcome the liabilities of artemisinin derivs.
- 179(a) Counter, F. T.; Ensminger, P. W.; Preston, D. A.; Wu, C. Y.; Greene, J. M.; Felty-Duckworth, A. M.; Paschal, J. W.; Kirst, H. A. Synthesis and antimicrobial evaluation of dirithromycin (AS-E 13. LY237216), a new macrolide antibiotic derived from erythromycin. Antimicrob. Agents Chemother. 1991, 35, 1116– 1126, DOI: 10.1128/AAC.35.6.1116[Crossref], [PubMed], [CAS], Google Scholar.179ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXks1Cisrk%253D&md5=e544a289268426d9ba07565d1e63e97eSynthesis and antimicrobial evaluation of dirithromycin (ASE 136; LY237216), a new macrolide antibiotic derived from erythromycinCounter, Fred T.; Ensminger, Paul W.; Preston, David A.; Wu, Chyun Yeh E.; Greene, James M.; Felty-Duckworth, Anna M.; Paschal, Jonathan W.; Kirst, Herbert A.Antimicrobial Agents and Chemotherapy (1991), 35 (6), 1116-26CODEN: AMACCQ; ISSN:0066-4804.Dirithromycin (I) is a 9-N-11-O-oxazine deriv. which is formed by condensation of 9(S)-erythromycylamine with 2-(2-methoxyethoxy)acetaldehyde. I is hydrolyzed, either under acidic conditions or in vivo, to its major active metabolite, 9(S)-erythromycylamine. The antimicrobial spectrum of I is similar to that of erythromycin; both antibiotics are active against gram-pos. bacteria, Legionella spp., Helicobacter pylori, and Chlamydia trachomatis. Comparable results were obtained for each antibiotic in MIC and MBC detns. and in the potential development of resistance in vitro. The effects of human serum, bacterial growth media, test methodol., and inoculum size on MICs were similar for each antibiotic. In std. mouse protection studies, I was more efficaceous than erythromycin against exptl. infections after s.c. administration of antibiotic. These results were consistent with pharmacokinetic studies in rodents, which showed that I gave more persistent concns. of antibiotic in serum and tissues than were achieved with erythromycin. These studies indicate that I possesses antimicrobial activity comparable to that of erythromycin in vitro but is more active than erythromycin in vivo, which may be attributable to the persistence of antimicrobial activity in the tissue(s) of the test animals.(b) Mazzei, T.; Surrenti, C.; Novelli, A.; Biagini, M. R.; Fallani, S.; Cassetta, M. I.; Conti, S.; Surrenti, E. Pharmacokinetics of dirithromycin in patients with mild or moderate cirrhosis. Antimicrob. Agents Chemother. 1999, 43, 1556– 1559, DOI: 10.1128/AAC.43.7.1556[Crossref], [PubMed], [CAS], Google Scholar.179bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXktlCksrs%253D&md5=904d030556bc51a68a766b83954662fePharmacokinetics of dirithromycin in patients with mild or moderate cirrhosisMazzei, Teresita; Surrenti, Calogero; Novelli, Andrea; Biagini, Maria Rosa; Fallani, Stefania; Cassetta, Maria Iris; Conti, Silvia; Surrenti, ElisabettaAntimicrobial Agents and Chemotherapy (1999), 43 (7), 1556-1559CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)The pharmacokinetics of dirithromycin were detd. over a 72-h period following oral administration of a single 500-mg dose to healthy volunteers and to cirrhotic patients (patients with class A cirrhosis and patients with class B cirrhosis according to Pugh's & Child's classification). Drug levels in plasma and urine were detd. by microbiol. assay. The mean max. concns. of drug in serum obtained 3-4 h after administration were 0.29 mg/L in volunteers and 0.48 and 0.52 mg/L in patients with class A and class B cirrhosis, resp. The elimination half-life (t1/2β) was 23.3 h in healthy subjects and 35.2 h and 39.5 h in patients with class A and class B cirrhosis, resp. The mean area under the concn.-time curve (AUC) and t1/2β were higher in patients with class A and B cirrhosis than in healthy controls, while total and renal clearances were markedly reduced. The time required to reach the max. concn. of drug in serum and the vol. of distribution appeared to be similar in all groups, and the mean recovery in urine after 72 h ranged 3.7-5.7% of the dose, without significant differences among groups. These results demonstrate that some dirithromycin kinetic parameters are significantly different in cirrhotic patients in comparison to those in healthy volunteers. However, the increase in the t1/2β or AUC, which has also been obsd. with other semisynthetic macrolides (e.g., azithromycin), does not seem to be clin. relevant if one takes into account both the high therapeutic indexes of these antibiotics and the usually short duration of therapy. Therefore, on the limited basis of single-dose administration, no modifications of dirithromycin dosage seem to be required even for patients with class B liver cirrhosis.(c) Sides, G. D.; Cerimele, B. J.; Black, H. R.; Bosch, U.; DeSante, K. A. Pharmacokinetics of dirithromycin. J. Antimicrob. Chemother. 1993, 31, 65– 75, DOI: 10.1093/jac/31.suppl_C.65[Crossref], [PubMed], [CAS], Google Scholar.179chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3sXisVKrurs%253D&md5=47dbb7ffd00decdd57361433f0946012Pharmacokinetics of dirithromycinSides, Gregory D.; Cerimele, Benito J.; Black, Henry R.; Busch, Ulrich; DeSante, Karl A.Journal of Antimicrobial Chemotherapy (1993), 31 (Suppl. C), 65-75CODEN: JACHDX; ISSN:0305-7453.The human pharmacokinetics and clin. pharmacol. of dirithromycin were studied. Dirithromycin has unique pharmacokinetics which distinguish it from erythromycin. In man, following an oral 500-mg dose of dirithromycin, a mean peak plasma concn. (Cmax) of 0.48 mg/L (range 0.1-1.97) was obsd. at 4 h. The mean area under the plasma concn. vs. time curve (AUC0-24h) was 3.37 mg.h/L. No plasma accumulation was obsd. with multiple-dose administration. Dirithromycin may be taken without regard to meals, although food and H2-receptor antagonists may increase the systemic bioavailability in some patients. Based upon drug interaction studies performed with antipyrine and theophylline, dirithromycin showed less potential to interact with other drugs metabolized by the cytochrome P 450 system than did erythromycin. Plasma concns. and AUCs were low due to rapid movement of the drug from the vascular space to the extravascular compartment, as reflected by tissue concns., which exceeded plasma concns. 4 h after administration. Dirithromycin achieved relatively high tissue concns. (0.8-5.0 mg/kg) 4-24 h after administration. The extensive tissue penetration was reflected in a large mean apparent vol. of distribution of 800 L. Dirithromycin was rapidly converted by nonenzymic hydrolysis during absorption to erythromycylamine, which is microbiol. active. In a 14C-radiolabeled study, 60-90% of the administered dose was hydrolyzed to erythromycylamine within 35 min of infusion. After 1.5 h, conversion to erythromycylamine in serum was virtually complete. Plasma protein binding was 15-30%. Dirithromycin was characterized by a plasma elimination half-life of 44 h that permits once-daily administration. Total-body clearance was 226-1040 mL/min. The primary route of elimination of dirithromycin/erythromycylamine was fecal/hepatic. Following i.v. administration, approx. 17-25% of the radioactivity appeared in the urine and 62-81% appeared in the stools, indicating predominantly hepatic excretion. With oral administration 1.2-2.9% of the radioactivity appeared in the urine and 81-97% in the stools. The major part of urinary excretion occurred within the 1st 48 h postadministration; however, urinary excretion of radioactivity lasted >40 h. The abs. bioavailability calcd. from dose-cor. urinary excretion data was 10% (6-14%).(d) Shinkai, I.; Ohta, Y. Dirithromycin. Bioorg. Med. Chem. 1996, 4, 521– 522, DOI: 10.1016/0968-0896(96)00052-1[Crossref], [PubMed], [CAS], Google Scholar179dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XjtlWqs7s%253D&md5=e88125aa45c2cc268474eaa6d955996fDirithromycinShinkai, Ichiro; Ohta, YukariBioorganic & Medicinal Chemistry (1996), 4 (4), 521-522CODEN: BMECEP; ISSN:0968-0896. (Elsevier)The antibiotic action of dirithromycin, recently approved by the FDA, is discussed.
- 180(a) Khabibullina, N. F.; Tereshchenkov, A. G.; Komarova, E. S.; Syroegin, E. A.; Shiriaev, D. I.; Paleskava, A.; Kartsev, V. G.; Bogdanov, A. A.; Konevega, A. L.; Dontsova, O. A.; Sergiev, P. V.; Osterman, I. A.; Polikanov, Y. S. Structure of dirithromycin bound to the bacterial ribosome suggests new ways for rational improvement of macrolides. Antimicrob. Agents Chemother. 2019, 63, e02266 DOI: 10.1128/AAC.02266-18[Crossref], [PubMed], [CAS], Google Scholar.180ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhs1Smsr7J&md5=2398cfdb39103a5d78c2a833286fbbd6Structure of dirithromycin bound to the bacterial ribosome suggests new ways for rational improvement of macrolidesKhabibullina, Nelli F.; Tereshchenkov, Andrey G.; Komarova, Ekaterina S.; Syroegin, Egor A.; Shiriaev, Dmitrii I.; Paleskava, Alena; Kartsev, Victor G.; Bogdanov, Alexey A.; Konevega, Andrey L.; Dontsova, Olga A.; Sergiev, Petr V.; Osterman, Ilya A.; Polikanov, Yury S.Antimicrobial Agents and Chemotherapy (2019), 63 (6), e02266-18/1-e02266-18/8CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)Although macrolides are known as excellent antibacterials, their medical use has been significantly limited due to the spread of bacterial drug resistance. Therefore, it is necessary to develop new potent macrolides to combat the emergence of drug-resistant pathogens. One of the key steps in rational drug design is the identification of chem. groups that mediate binding of the drug to its target and their subsequent derivatization to strengthen drug-target interactions. In the case of macrolides, a few groups are known to be important for drug binding to the ribosome, such as desosamine. Search for new chem. moieties that improve the interactions of a macrolide with the 70S ribosome might be of crucial importance for the invention of new macrolides. For this purpose, here we studied a classic macrolide, dirithromycin, which has an extended (2-methoxyethoxy)-Me side chain attached to the C-9/C-11 atoms of the macrolactone ring that can account for strong binding of dirithromycin to the 70S ribosome. By solving the crystal structure of the 70S ribosome in complex with dirithromycin, we found that its side chain interacts with the wall of the nascent peptide exit tunnel in an idiosyncratic fashion: its side chain forms a lone pair-π stacking interaction with the arom. imidazole ring of the His69 residue in ribosomal protein uL4. To our knowledge, the ability of this side chain to form a contact in the macrolide binding pocket has not been reported previously and potentially can open new avenues for further exploration by medicinal chemists developing next-generation macrolide antibiotics active against resistant pathogens.(b) Pichkur, E. B.; Paleskava, A.; Tereshchenkov, A. G.; Kasatsky, P.; Komarova, E. S.; Shiriaev, D. I.; Bogdanov, A. A.; Dontsova, O. A.; Osterman, I. A.; Sergiev, P. V.; Polikanov, Y. S.; Myasnikov, A. G.; Konevega, A. L. Insights into the improved macrolide inhibitory activity from the high-resolution cryo-EM structure of dirithromycin bound to the E. coli 70S ribosome. RNA 2020, 26, 715– 723, DOI: 10.1261/rna.073817.119[Crossref], [PubMed], [CAS], Google Scholar180bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXit1KlsbjN&md5=9d3e3c6c0d8ef3835fdb7a27a0e9a0e9Insights into the improved macrolide inhibitory activity from the high-resolution cryo-EM structure of dirithromycin bound to the E. coli 70S ribosomePichkur, Evgeny B.; Paleskava, Alena; Tereshchenkov, Andrey G.; Kasatsky, Pavel; Komarova, Ekaterina S.; Shiriaev, Dmitrii I.; Bogdanov, Alexey A.; Dontsova, Olga A.; Osterman, Ilya A.; Sergiev, Petr V.; Polikanov, Yury S.; Myasnikov, Alexander G.; Konevega, Andrey L.RNA (2020), 26 (6), 715-723CODEN: RNARFU; ISSN:1355-8382. (Cold Spring Harbor Laboratory Press)Macrolides are one of the most successful and widely used classes of antibacterials, which kill or stop the growth of pathogenic bacteria by binding near the active site of the ribosome and interfering with protein synthesis. Dirithromycin is a deriv. of the prototype macrolide erythromycin with addnl. hydrophobic side chain. In our recent study, we have discovered that the side chain of dirithromycin forms lone pair-π stacking interaction with the arom. imidazole ring of the His69 residue in ribosomal protein uL4 of the Thermus thermophilus 70S ribosome. In the current work, we found that neither the presence of the side chain, nor the addnl. contact with the ribosome, improve the binding affinity of dirithromycin to the ribosome. Nevertheless, we found that dirithromycin is a more potent inhibitor of in vitro protein synthesis in comparison with its parent compd., erythromycin. Using high-resoln. cryo-electron microscopy, we detd. the structure of the dirithromycin bound to the translating Escherichia coli 70S ribosome, which suggests that the better inhibitory properties of the drug could be rationalized by the side chain of dirithromycin pointing into the lumen of the nascent peptide exit tunnel, where it can interfere with the normal passage of the growing polypeptide chain.
- 181(a) Wöhr, T.; Wahl, F.; Nefzi, A.; Rohwedder, B.; Sato, T.; Sun, X.; Mutter, M. Pseudo-prolines as a solubilizing, structure-disrupting protection technique in peptide synthesis. J. Am. Chem. Soc. 1996, 118, 9218– 9227, DOI: 10.1021/ja961509q .(b) Chaume, G.; Barbeau, O.; Lesot, P.; Brigaud, T. Synthesis of 2-trifluoromethyl-1,3-oxazolidines as hydrolytically stable pseudoprolines. J. Org. Chem. 2010, 75, 4135– 4145, DOI: 10.1021/jo100518t[ACS Full Text.], [CAS], Google Scholar181bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXmt12murg%253D&md5=ee99f09126da653cb834ba460fb4d8dbSynthesis of 2-trifluoromethyl-1,3-oxazolidines as hydrolytically stable pseudoprolinesChaume, Gregory; Barbeau, Olivier; Lesot, Philippe; Brigaud, ThierryJournal of Organic Chemistry (2010), 75 (12), 4135-4145CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)Trifluoromethyl group contg. oxazolidines (Fox) are conveniently synthesized by condensation of serine esters with trifluoroacetaldehyde hemiacetal or trifluoroacetone. These oxazolidines can undergo N-acylation and amidification reactions and are completely configurationally and hydrolytically stable. Therefore, they can be considered as highly valuable proline surrogates (Tfm-pseudoprolines).(c) Malquin, N.; Rahgoshay, K.; Lensen, N.; Chaume, G.; Miclet, E.; Brigaud, T. CF2H as a hydrogen bond donor group for the fine tuning of peptide bond geometry with difluoromethylated pseudoprolines. Chem. Commun. 2019, 55, 12487– 12490, DOI: 10.1039/C9CC05771D[Crossref], [PubMed], [CAS], Google Scholar.181chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvVersb7L&md5=5a3f14e2aec4ffe19922d4e23ac397e5CF2H as a hydrogen bond donor group for the fine tuning of peptide bond geometry with difluoromethylated pseudoprolinesMalquin, N.; Rahgoshay, K.; Lensen, N.; Chaume, G.; Miclet, E.; Brigaud, T.Chemical Communications (Cambridge, United Kingdom) (2019), 55 (83), 12487-12490CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)CF2H-Pseudoprolines obtained from difluoroacetaldehyde hemiacetal and serine are stable proline surrogates. The consequence of the incorporation of the CF2H group is an important decrease of the trans to cis amide bond isomerization energy and a remarkable stabilization of the cis conformer by an hydrogen bond.(d) Chaume, G.; Simon, J.; Caupéne, C.; Lensen, N.; Miclet, E.; Brigaud, T. Incorporation of CF3-pseudoprolines into peptides: a methodological study. J. Org. Chem. 2013, 78, 10144– 10153, DOI: 10.1021/jo401494q[ACS Full Text], [CAS], Google Scholar181dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVeksbbL&md5=21e72f67a8e6a6302632e3c062ef7dd7Incorporation of CF3-Pseudoprolines into Peptides: A Methodological StudyChaume, Gregory; Simon, Julien; Caupene, Caroline; Lensen, Nathalie; Miclet, Emeric; Brigaud, ThierryJournal of Organic Chemistry (2013), 78 (20), 10144-10153CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)The peptide coupling reactions allowing the incorporation of trifluoromethyl substituted oxazolidine-type pseudoprolines (CF3-ΨPro) into peptide chains have been studied. While std. protocols can be used for the peptide coupling reaction at the C-terminal position of the CF3-ΨPro, acid chloride activation has to be used for the peptide coupling reaction at the N-terminal position to overcome the decrease of nucleophilicity of the CF3-ΨPro. The authors demonstrate that the N-amidification of a diastereomeric mixt. of CF3-ΨPro using Fmoc-protected amino acid chloride without base gave the corresponding dipeptides as a single diastereomer (6 examples). The ratio of the cis and trans amide bond conformers was detd. by NMR study, highlighting the role of the Xaa side chains in the control of the peptide backbone conformation. Finally a tripeptide bearing a central CF3-ΨPro has been successfully synthesized.
- 182(a) Coburn, C. A.; Meinke, P. T.; Chang, W.; Fandozzi, C. M.; Graham, D. J.; Hu, B.; Huang, Q.; Kargman, S.; Kozlowski, J.; Liu, R.; McCauley, J. A.; Nomeir, A. A.; Soll, R. M.; Vacca, J. P.; Wang, D.; Wu, H.; Zhong, B.; Olsen, D. B.; Ludmerer, S. W. Discovery of MK-8742: an HCV NS5A inhibitor with broad genotype activity. ChemMedChem 2013, 8, 1930– 1940, DOI: 10.1002/cmdc.201300343[Crossref], [PubMed], [CAS], Google Scholar.182ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhs1SkurzN&md5=2f2b3ed2281c43e39b24d4197b9f57eeDiscovery of MK-8742: An HCV NS5A inhibitor with broad genotype activityCoburn, Craig A.; Meinke, Peter T.; Chang, Wei; Fandozzi, Christine M.; Graham, Donald J.; Hu, Bin; Huang, Qian; Kargman, Stacia; Kozlowski, Joseph; Liu, Rong; McCauley, John A.; Nomeir, Amin A.; Soll, Richard M.; Vacca, Joseph P.; Wang, Dahai; Wu, Hao; Zhong, Bin; Olsen, David B.; Ludmerer, Steven W.ChemMedChem (2013), 8 (12), 1930-1940CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)The NS5A protein plays a crit. role in the replication of HCV and has been the focus of numerous research efforts over the past few years. NS5A inhibitors have shown impressive in vitro potency profiles in HCV replicon assays, making them attractive components for inclusion in all oral combination regimens. Early work in the NS5A arena led to the discovery of our first clin. candidate, MK-4882 [2-((S)-pyrrolidin-2-yl)-5-(2-(4-(5-((S)-pyrrolidin-2-yl)-1H-imidazol-2-yl)phenyl)benzofuran-5-yl)-1H-imidazole]. While preclin. proof-of-concept studies in HCV-infected chimpanzees harboring chronic genotype 1 infections resulted in significant decreases in viral load after both single- and multiple-dose treatments, viral breakthrough proved to be a concern, thus necessitating the development of compds. with increased potency against a no. of genotypes and NS5A resistance mutations. Modification of the MK-4882 core scaffold by introduction of a cyclic constraint afforded a series of tetracyclic inhibitors, which showed improved virol. profiles. Herein we describe the research efforts that led to the discovery of MK-8742, a tetracyclic indole-based NS5A inhibitor, which is currently in phase 2b clin. trials as part of an all-oral, interferon-free regimen for the treatment of HCV infection.(b) Yu, W.; Tong, L.; Hu, B.; Zhong, B.; Hao, J.; Ji, T.; Zan, S.; Coburn, C. A.; Selyutin, O.; Chen, L.; Rokosz, L.; Agrawal, S.; Liu, R.; Curry, S.; McMonagle, P.; Ingravallo, P.; Asante-Appiah, E.; Chen, S.; Kozlowski, J. A. Discovery of chromane containing hepatitis C virus (HCV) NS5A inhibitors with improved potency against resistance-associated variants. J. Med. Chem. 2016, 59, 10228– 10243, DOI: 10.1021/acs.jmedchem.6b01234[ACS Full Text.], [CAS], Google Scholar182bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslGhu7zO&md5=6d6fa084bd50859fe090e42c545bc789Discovery of Chromane Containing Hepatitis C Virus (HCV) NS5A Inhibitors with Improved Potency against Resistance-Associated VariantsYu, Wensheng; Tong, Ling; Hu, Bin; Zhong, Bin; Hao, Jinglai; Ji, Tao; Zan, Shuai; Coburn, Craig A.; Selyutin, Oleg; Chen, Lei; Rokosz, Laura; Agrawal, Sony; Liu, Rong; Curry, Stephanie; McMonagle, Patricia; Ingravallo, Paul; Asante-Appiah, Ernest; Chen, Shiying; Kozlowski, Joseph A.Journal of Medicinal Chemistry (2016), 59 (22), 10228-10243CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The discovery of potent and pan-genotypic HCV NS5A inhibitors faces many challenges including the significant diversity among genotypes, substantial potency shift conferred on some key resistance-assocd. variants, inconsistent SARs between different genotypes and mutants, and the lacking of models of inhibitor/protein complexes for rational inhibitor design. As part of ongoing efforts on HCV NS5A inhibition at Merck, the authors now describe the discovery of a novel series of chromane contg. NS5A inhibitors. SAR studies around the "Z" group of the tetracyclic indole scaffold explored fused bicyclic rings as alternates to the Ph group of elbasvir (1, MK-8742) and identified novel chromane and 2,3-dihydrobenzofuran derivs. as "Z" group replacements offered good potency across all genotypes. This effort, incorporating the C-1 fluoro substitution at the tetracyclic indole core, led to the discovery of a new series of NS5A inhibitors with significantly improved potency against resistance-assocd. variants, such as GT2b, GT1a Y93H, and GT1a L31V. Compd. 14 (di-Me ((2S,2'S)-((2S,2'S)-((6-(Chroman-7-yl)-1-fluoro-6H-benzo[5,6][1,3]oxazino[3,4-a]indole-3,10-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobu-tane-1,2-diyl))dicarbamate) also showed reasonable PK exposures in preclin. species (rat and dog).(c) Tong, L.; Yu, W.; Chen, L.; Selyutin, O.; Dwyer, M. P.; Nair, A. G.; Mazzola, R.; Kim, J.; Sha, D.; Yin, J.; Ruck, R. T.; Davies, R. W.; Hu, B.; Zhong, B.; Hao, J.; Ji, T.; Zan, S.; Liu, R.; Agrawal, S.; Xia, E.; Curry, S.; McMonagle, P.; Bystol, K.; Lahser, F.; Carr, D.; Rokosz, L.; Ingravallo, P.; Chen, S.; Feng, K.; Cartwright, M.; Asante-Appiah, E.; Kozlowski, J. A. Discovery of ruzasvir (MK-8408): a potent, pan-genotype HCV NS5A inhibitor with optimized activity against common resistance-associated polymorphisms. J. Med. Chem. 2017, 60, 290– 306, DOI: 10.1021/acs.jmedchem.6b01310[ACS Full Text.], [CAS], Google Scholar182chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhslygt7jN&md5=6224e41b940abfb96cda518ecebf3e0fDiscovery of Ruzasvir (MK-8408): A Potent, Pan-Genotype HCV NS5A Inhibitor with Optimized Activity against Common Resistance-Associated PolymorphismsTong, Ling; Yu, Wensheng; Chen, Lei; Selyutin, Oleg; Dwyer, Michael P.; Nair, Anilkumar G.; Mazzola, Robert; Kim, Jae-Hun; Sha, Deyou; Yin, Jingjun; Ruck, Rebecca T.; Davies, Ian W.; Hu, Bin; Zhong, Bin; Hao, Jinglai; Ji, Tao; Zan, Shuai; Liu, Rong; Agrawal, Sony; Xia, Ellen; Curry, Stephanie; McMonagle, Patricia; Bystol, Karin; Lahser, Frederick; Carr, Donna; Rokosz, Laura; Ingravallo, Paul; Chen, Shiying; Feng, Kung-I.; Cartwright, Mark; Asante-Appiah, Ernest; Kozlowski, Joseph A.Journal of Medicinal Chemistry (2017), 60 (1), 290-306CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The authors describe the research that led to the discovery of compd. 40 (ruzasvir, MK-8408), a pan-genotypic HCV nonstructural protein 5A (NS5A) inhibitor with a "flat" GT1 mutant profile. This NS5A inhibitor contains a unique tetracyclic indole core, while maintaining the imidazole-proline-valine Moc motifs of the authors' previous NS5A inhibitors. Compd. 40 is currently in early clin. trials and is under evaluation as part of an all-oral DAA regimen for the treatment of chronic HCV infection.(d) Yu, W.; Tong, L.; Selyutin, O.; Chen, L.; Hu, B.; Zhong, B.; Hao, J.; Ji, T.; Zan, S.; Yin, J.; Ruck, R. T.; Curry, S.; McMonagle, P.; Agrawal, S.; Rokosz, L.; Carr, D.; Ingravallo, P.; Bystol, K.; Lahser, F.; Liu, R.; Chen, S.; Feng, K.; Cartwright, M.; Asante-Appiah, E.; Kozlowski, J. A. Discovery of MK-6169, a potent pan-genotype hepatitis C virus NS5A inhibitor with optimized activity against common resistance-associated substitutions. J. Med. Chem. 2018, 61, 3984– 4003, DOI: 10.1021/acs.jmedchem.7b01927[ACS Full Text.], [CAS], Google Scholar182dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXotVahtro%253D&md5=9f8fb68f245d3e189136badeff91571eDiscovery of MK-6169, a Potent Pan-Genotype Hepatitis C Virus NS5A Inhibitor with Optimized Activity against Common Resistance-Associated SubstitutionsYu, Wensheng; Tong, Ling; Selyutin, Oleg; Chen, Lei; Hu, Bin; Zhong, Bin; Hao, Jinglai; Ji, Tao; Zan, Shuai; Yin, Jingjun; Ruck, Rebecca T.; Curry, Stephanie; McMonagle, Patricia; Agrawal, Sony; Rokosz, Laura; Carr, Donna; Ingravallo, Paul; Bystol, Karin; Lahser, Frederick; Liu, Rong; Chen, Shiying; Feng, Kung-I.; Cartwright, Mark; Asante-Appiah, Ernest; Kozlowski, Joseph A.Journal of Medicinal Chemistry (2018), 61 (9), 3984-4003CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)We describe the discovery of MK-6169 (I), a potent and pan-genotype hepatitis C virus NS5A inhibitor with optimized activity against common resistance-assocd. substitutions. SAR studies around the combination of changes to both the valine and aminal carbon region of elbasvir led to the discovery of a series of compds. with substantially improved potency against common resistance-assocd. substitutions in the major genotypes, as well as good pharmacokinetics in both rat and dog. Through further optimization of key leads from this effort, MK-6169 (I) was discovered as a preclin. candidate for further development.(e) https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208261Orig1s000PharmR.pdf (accessed April 2, 2021.)
- 183(a) Reading, C.; Cole, M. Clavulanic acid: a β-lactamase-inhibiting β-lactam from Streptomyces clavuligerus. Antimicrob. Agents Chemother. 1977, 11, 852– 857, DOI: 10.1128/AAC.11.5.852[Crossref], [PubMed], [CAS], Google Scholar.183ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE2sXks1GjtLw%253D&md5=f418af59b52360c0ffe187922c0ef99dClavulanic acid: a beta-lactamase-inhibiting beta-lactam from Streptomyces clavuligerusReading, C.; Cole, M.Antimicrobial Agents and Chemotherapy (1977), 11 (5), 852-7CODEN: AMACCQ; ISSN:0066-4804.A novel β-lactamase inhibitor has been isolated from S. clavuligerus ATCC 27064 and given the name clavulanic acid (I). Conditions for the cultivation of the organism and detection and isolation of I are described. This compd. resembles the nucleus of a penicillin but differs in having no acylamino side chain, having O instead of S, and contg. a β-hydroxyethylidine substituent in the oxazolidine ring. I is a potent inhibitor of many β-lactamases, including those found in Escherichia coli (plasmid mediated), Klebsiella aerogenes, Proteus mirabilis, and Staphylococcus aureus, the inhibition being of a progressive type. The cephalosporinase type of β-lactamase found in Pseudomonas aeruginosa and Enterobacter cloacae P99 and the chromosomally mediated β-lactamase of E. coli are less well inhibited. The min. inhibitory concns. of ampicillin and cephaloridine against β-lactamase-producing, penicillin-resistant strains of S. aureus, K. aerogenes, P. mirabilis, and E. coli are considerably reduced by the addn. of low concns. of I.(b) Buynak, J. D. Understanding the longevity of the β-lactam antibiotics and of antibiotic/β-lactamase inhibitor combinations. Biochem. Pharmacol. 2006, 71, 930– 940, DOI: 10.1016/j.bcp.2005.11.012[Crossref], [PubMed], [CAS], Google Scholar183bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XitVKjurc%253D&md5=003ecb0fa5b73a67115a6f081394fac7Understanding the longevity of the β-lactam antibiotics and of antibiotic/β-lactamase inhibitor combinationsBuynak, John D.Biochemical Pharmacology (2006), 71 (7), 930-940CODEN: BCPCA6; ISSN:0006-2952. (Elsevier B.V.)A review. Microbial resistance necessitates the search for new targets and new antibiotics. However, it is likely that resistance problems will eventually threaten these new products and it may, therefore, be instructive to review the successful employment of β-lactam antibiotic/β-lactamase inhibitor combinations to combat penicillin resistance. These combination drugs have proven successful for more than two decades, with inhibitor resistance still being relatively rare. The β-lactamase inhibitors are mechanism-based irreversible inactivators. The ability of the inhibitors to avoid resistance may be due to the structural similarities between the substrate and inhibitor.
- 184(a) Brown, R. P.; Aplin, R. T.; Schofield, C. J. Inhibition of TEM-2 β-lactamase from Escherichia coli by clavulanic acid: observation of intermediates by electrospray ionization mass spectrometry. Biochemistry 1996, 35, 12421– 12432, DOI: 10.1021/bi961044g[ACS Full Text.], [CAS], Google Scholar184ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XltlCqs7c%253D&md5=eda160601cb775ff61d402f6d34c6050Inhibition of TEM-2 β-lactamase from Escherichia coli by clavulanic acid: observation of intermediates by electrospray ionization mass spectrometryBrown, Roland P. A.; Aplin, Robin T.; Schofield, Christopher J.Biochemistry (1996), 35 (38), 12421-12432CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)Clavulanic acid, the therapeutically important inhibitor of β-lactamases contg. a nucleophilic serine residue at their active sites, inhibits Escherichia coli TEM-2 β-lactamase via a complex mechanism. Electrospray ionization mass spectrometry (ESIMS) studies revealed that a min. of four different modified proteins are formed upon incubation of clavulanate with the TEM-2 enzyme. These exhibit mass increments relative to the unmodified TEM-2 β-lactamase of 52, 70, 88, and 155 Da. Time course studies implied that no long-lived forms of clavulanate-inhibited TEM-2 β-lactamase retain the carbons of the oxazolidine ring of clavulanate. The absence of a 199-Da increment to unmodified TEM-2 suggests rapid decarboxylation of clavulanate upon binding to the enzyme. Proteolytic digestions of purified forms of clavulanate inhibited TEM-2 β-lactamase followed by analyses using HPLC coupled to ESIMS (HPLC-ESIMS) and chem. sequencing were used to provide positional information on the modifications to the enzyme. Increments of 70 and 80-Da increments were shown to be located in a peptide contg. Ser 70. A further 70-Da mass increment, assigned as a β-linked acrylate, was localized to a peptide contg. Ser 130. A mechanistic scheme for the reaction of clavulanate with TEM-2 β-lactamase is proposed in which acylation at Ser 70 and subsequent decarboxylation is followed either by crosslinking with Ser 130 to form a vinyl ether or by reformation of unmodified enzyme via a Ser 70 linked (hydrated) aldehyde. Purified crosslinked vinyl ether was obsd. to slowly convert under acidic conditions to a Ser 70 linked (hydrated) aldehyde with concomitant conversion of Ser 130 to a dehydroalanine residue.(b) Imtiaz, U.; Billings, E.; Knox, J. R.; Manavathu, E. K.; Lerner, S. A.; Mobashery, S. Inactivation of class A β-lactamases by clavulanic acid: the role of arginine-244 in a proposed nonconcerted sequence of events. J. Am. Chem. Soc. 1993, 115, 4435– 4442, DOI: 10.1021/ja00064a003[ACS Full Text], [CAS], Google Scholar184bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3sXisFSnsr0%253D&md5=672b2943e1d3e8490a0aa1bafe41e305Inactivation of class A β-lactamases by clavulanic acid: the role of arginine-244 in a proposed nonconcerted sequence of eventsImtiaz, Uzma; Billings, Eric; Knox, James R.; Manavathu, Elias K.; Lerner, Stephen A.; Mobashery, ShahriarJournal of the American Chemical Society (1993), 115 (11), 4435-42CODEN: JACSAT; ISSN:0002-7863.From the refined 2-Å crystal structure of β-lactamase (I) of Bacillus licheniformis 749/C, which shares a high sequence homol. with TEM-1 I, energy-minimized models for active site binding of the precatalytic (Michaelis) complex with the clin. utilized inactivator, clavulanic acid (II), for the acyl-enzyme intermediate, and for the ultimate acylated acyclic species that leads to inactivation of class A I by II were generated. On the basis of these models, the details of the chem. of I inactivation by II were reassessed. A nonconcerted mechanism for the inactivation chem. of class A I by II was proposed. These models revealed that the Arg-244 side-chain and the Val-216 carbonyl anchor a structurally conserved water mol., W673, which serves as the most likely source of a crit. proton in a stepwise sequence of events. Disruption of this electrostatic anchor for W673 by mutational replacement of Arg-244 with Ser in TEM I would account for the resulting obsd. severe impairment of the efficiency of inactivation of the mutant enzyme by II. The kinetic impact of the Arg-244-Ser mutation on interaction with II was reflected by resistance to ampicillin plus II of a strain of Escherichia coli bearing the mutant enzyme. Mol. dynamics computations on the acylated acyclic intermediate, the putative inactivating species, indicated that irreversible inactivation of I may not occur as a consequence of a transimination reaction, in contrast to previous suggestions. The most likely scenario for irreversible inactivation involves the capture of the β-OH group of conserved Ser-130 by the iminium moiety of the acylated acyclic intermediate, followed by deprotonation at C6 of II. The deprotonation is likely to be carried out by the conserved Glu-166 via the intervening crystallog. water W712. Deprotonation prior to nucleophile capture is proposed as the mechanism of generation of the so-called transiently inhibited enamine species. For wild-type TEM-1 I, both irreversible inactivation and the formation of the transiently inhibited species proceed with comparable rates. In addn., a new function for the Ser-130 in the formation of the acyl-enzyme intermediate with both II and typical I substrates is proposed. It is suggested that the β-OH group of Ser-130 stabilizes the transition state for the expulsion of the incipient amine from the high-energy tetrahedral species by H-bonding to the oxazolidine amine in the course of Ser-70 acylation.
- 185Haginaka, J.; Nakagawa, T.; Uno, T. Stability of clavulanic acid in aqueous solutions. Chem. Pharm. Bull. 1981, 29, 3334– 3341, DOI: 10.1248/cpb.29.3334[Crossref], [CAS], Google Scholar185https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL38XlslKlsA%253D%253D&md5=f9ab8243de4406223ee81ddf32d996feStability of clavulanic acid in aqueous solutionsHaginaka, Jun; Nakagawa, Terumichi; Uno, ToyozoChemical & Pharmaceutical Bulletin (1981), 29 (11), 3334-41CODEN: CPBTAL; ISSN:0009-2363.The stability of clavulanic acid (I) [58001-44-8] in aq. solns. was investigated over a pH range of 3.15 to 10.10 at 35° and at an ionic strength of 0.5. The changes in the concn. of intact I in buffer solns. were detd. by reversed phase HPLC with UV-detection using a mobile phase contg. Bu4NBr. The obsd. degrdn. rates at various pH's followed pseudo-first-order kinetics, and were significantly affected by catalysis due to buffer salts. The catalytic rate consts. were estd. at 3 different concns. of buffer systems. The pH vs. rate profiles obtained from non-buffer-catalyzed rate consts., kpH, revealed that the degrdn. in alk. solns. proceeded, as a whole, about 10 times faster than in acidic media, and max. stability was attained at pH 6.39. The Arrhenius activation energies at pH 3.94, 6.67, and 8.74 were est. as 19.0, 14.7, and 18.3 kcal/mol., resp.
- 186(a) Adam, D.; de Visser, I.; Koeppe, P. Pharmacokinetics of amoxicillin and clavulanic acid administered alone and in combination. Antimicrob. Agents Chemother. 1982, 22, 353– 357, DOI: 10.1128/AAC.22.3.353[Crossref], [PubMed], [CAS], Google Scholar.186ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL3sXmsFShtA%253D%253D&md5=2914359f7c115fa0bfd9a2afb6ac1c28Pharmacokinetics of amoxicillin and clavulanic acid administered alone and in combinationAdam, Dieter; De Visser, Iris; Koeppe, PeterAntimicrobial Agents and Chemotherapy (1982), 22 (3), 353-7CODEN: AMACCQ; ISSN:0066-4804.The pharmacokinetics of amoxicillin (I) [26787-78-0] and clavulanic acid (II) [58001-44-8], administered alone and as a I-II mixt. [74469-00-4], were studied in normal human volunteers. Each ingested 500 mg of I or 125 mg of II or the I-II mixt. in randomized sequence. The results indicate that most of the parameters tested for either substance are essentially independent of the presence of the other one.(b) Navarro, A. S. New formulations of amoxicillin/clavulanic acid. Clin. Pharmacokinet. 2005, 44, 1097– 1115, DOI: 10.2165/00003088-200544110-00001 .(c) De Velde, F.; De Winter, B. C. M.; Koch, B. C. P.; Van Gelder, T.; Mouton, J. W. and the COMBACTE-NET consortium. Highly variable absorption of clavulanic acid during the day: a population pharmacokinetic analysis. J. Antimicrob. Chemother. 2018, 73, 469– 476, DOI: 10.1093/jac/dkx376[Crossref], [PubMed], [CAS], Google Scholar186chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitlCjsr3F&md5=ad77302f46166a7d8f9763b44b018ea8Highly variable absorption of clavulanic acid during the day:a population pharmacokinetic analysisDe Velde, Femke; De Winter, Brenda C. M.; Koch, Birgit C. P.; Van Gelder, Teun; Mouton, Johan W.Journal of Antimicrobial Chemotherapy (2018), 73 (2), 469-476CODEN: JACHDX; ISSN:1460-2091. (Oxford University Press)Objectives: To calc. the clavulanic acid exposure of oral amoxicillin/clavulanic acid dosing regimens, to investigate variability using a population pharmacokinetic model and to explore target attainment using Monte Carlo simulations. Methods: Two groups of healthy male volunteers received amoxicillin/clavulanic acid tablets at the start of a std. meal on two sep. days 1 wk apart. One group (n=14) received 875/125mg q12h and 500/125mg q8h and the other group (n=15) received 500/125mg q12h and 250/125mg q8h. In total, 1479 blood samples were collected until 8-12 h after administration. Concns. were analyzed using non-compartmental (WinNonLin) and population pharmacokinetic (NONMEM) methods. Results: Median Cmax and AUC0-8 were 2.21mg/L (0.21-4.35) and 4.99 mg·h/L (0.44-8.31), resp. In 40/58 daily concn.-time profiles, Cmax and AUC0-8 of the morning dose were higher than with later doses.The final population model included a lag time (0.447 h), first-order absorption (3.99 h-1 at 8:00 h, between subject variability 52.8%, between-occasion variability 48.5%), one distribution compartment (33.0 L, between subject variability 23.9%) and first-order elimination (24.6 L/h, between-subject variability 26.7%). Bioavailability (fixed at 1 at 8:00 h, between-occasion variability 28.2%) and absorption rate decreased over the day. For 97.5% of the simulated population after 125mg q12h or q8h, %fT>Ct at 0.5mg/L was 8.33% (q12h) and 15.2% (q8h), %fT>Ct at 1mg/Lwas 0%(q12h+q8h), and fAUC0-24 was 3.61 (q12h) and 5.56 (q8h) mg·h/L. Conclusions: Clavulanic acid absorption in healthy volunteers is highly variable. Bioavailability and absorption rate decrease over the day. The model developed here may serve to suggest clavulanic acid dosing regimens to optimize efficacy and prevent underdosing.
- 187(a) Krishnan, B. R.; James, K. D.; Polowy, K.; Bryant, B.; Vaidya, A.; Smith, S.; Laudeman, C. P. CD101, a novel echinocandin with exceptional stability properties and enhanced aqueous solubility. J. Antibiot. 2017, 70, 130– 135, DOI: 10.1038/ja.2016.89[Crossref], [PubMed], [CAS], Google Scholar.187ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhs1ait78%253D&md5=538cd97a5dcc6307960567417d8b5ab2CD101, a novel echinocandin with exceptional stability properties and enhanced aqueous solubilityKrishnan, B. Radha; James, Kenneth D.; Polowy, Karen; Bryant, B. J.; Vaidya, Anu; Smith, Steve; Laudeman, Christopher P.Journal of Antibiotics (2017), 70 (2), 130-135CODEN: JANTAJ; ISSN:0021-8820. (Nature Publishing Group)The echinocandins are an important class of antifungal agents. However, instability and, in some cases, lack of soly. have restricted their use to situations in which daily infusions are acceptable. CD101 is a novel echinocandin in development for topical and weekly i.v. administration that exhibits prolonged stability in plasma and aq. solns. up to 40°. After incubation for 44 h in rat, dog, monkey and human plasma at 37°, the percent of CD101 remaining (91%, 79%, 94% and 93%, resp.) was consistently greater than that of anidulafungin (7%, 15%, 14% and 7%, resp.). Similarly, after incubation in phosphate-buffered saline at 37°, the CD101 remaining (96%) was greater than that of anidulafungin (42%). CD101 exhibited <2% degrdn. after long-term storage at 40° as a lyophilized powder (9 mo) and at room temp. in 5% dextrose (15 mo), 0.9% saline (12 mo) and sterile water (18 mo). Degrdn. was <7% at 40° in acetate and lactate buffers (6 to 9 mo at pH 4.5-5.5). The chem. stability and soly. of CD101 contribute to dosing, pharmacokinetic, formulation and safety advantages over other echinocandins and should expand utility beyond daily i.v. therapy.(b) Sofjan, A. K.; Mitchell, A.; Shah, D. N.; Nguyen, T.; Sim, M.; Trojcak, A.; Beyda, N. D.; Garey, K. W. Rezafungin (CD101), a next-generation echinocandin: A systematic literature review and assessment of possible place in therapy. J. Global Antimicrob. Resist. 2018, 14, 58– 64, DOI: 10.1016/j.jgar.2018.02.013[Crossref], [PubMed], [CAS], Google Scholar187bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1MrlvFSjsA%253D%253D&md5=34824f471858dbb7add390cfbb93c5cbRezafungin (CD101), a next-generation echinocandin: A systematic literature review and assessment of possible place in therapySofjan Amelia K; Mitchell Ardath; Shah Dhara N; Nguyen Tam; Sim Mui; Trojcak Ashley; Beyda Nicholas D; Garey Kevin WJournal of global antimicrobial resistance (2018), 14 (), 58-64 ISSN:.OBJECTIVES: Rezafungin (CD101) is a novel echinocandin currently under development. The purpose of this study was to perform a systematic literature review of published evidence on rezafungin and an antimicrobial stewardship audit of real-world use of echinocandins to determine areas of unmet medical needs and potential places in therapy for rezafungin. METHODS: The systematic literature review identified 8 peer-reviewed manuscripts and 19 separate abstracts. A stewardship audit was performed on hospitalised patients receiving echinocandins to better understand potential future areas of use for rezafungin. RESULTS: Rezafungin is a cyclic hexapeptide with a lipophilic tail derived from anidulafungin, with a choline moiety at the C5 ornithine position resulting in increased in vitro and in vivo stability compared with other echinocandins. Microbiological data showed similar susceptibility and resistance development between rezafungin and other echinocandins. Rezafungin has a long half-life (80h) and a favourable safety profile that allows for high doses (up to 400mg) given once weekly. A phase 2 study is ongoing. The antimicrobial stewardship audit of echinocandin identified several areas of possible use for rezafungin, including patients receiving daily echinocandins for >7 days, patients who remained in the hospital to complete a full course of daily echinocandin therapy, and patients who required an echinocandin scheduled via an infusion clinic after discharge. CONCLUSION: Rezafungin is a novel echinocandin currently in phase 2 studies, differentiated by a long half-life that allows once-weekly dosing and a safety profile that allows higher doses. Several potential areas of use for rezafungin were identified.
- 188Kofla, G.; Ruhnke, M. Pharmacology and metabolism of anidulafungin, caspofungin and micafungin in the treatment of invasive candidosis: review of the literature. Eur. J. Med.Res. 2011, 16, 159– 166, DOI: 10.1186/2047-783X-16-4-159[Crossref], [PubMed], [CAS], Google Scholar188https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXot1OhtLw%253D&md5=71507c21beeb35f67464739857c110e2Pharmacology and metabolism of anidulafungin, caspofungin and micafungin in the treatment of invasive candidosis - review of the literatureKofla, G.; Ruhnke, M.European Journal of Medical Research (2011), 16 (4), 159-166CODEN: EJMRFL; ISSN:0949-2321. (I. Holzapfel Verlag GmbH)A review. Echinocandins represent the newest class of antifungal agents. Currently, three echinocandins, anidulafungin, caspofungin and micafungin are licensed for clin. use in various indications. They act as inhibitors of β-(1,3)-glucan synthesis in the fungal cell wall and have a favorable pharmacol. profile. They have a broad spectrum of activity against all Candida species. Higher MIC's have been obsd. against C. parapsilosis and C. guilliermondii. Data from clin. trials for invasive Candida infections / candidemia suggest that the clin. outcome of patients treated with either drug may be very similar. A comparison has been done between caspofungin and micafungin but for anidulafungin a comparative trial with another echinocandin is still lacking. All three drugs are highly effective if not superior to treatment with either fluconazole or Amphotericin B, particularly in well-defined clin. settings such as invasive Candida infections, Candida oesophagitis and candidemia. Differences between the three echinocandins with regard to the route of metab., requirement for a loading dose, dose adjustment in patients with moderate to severe hepatic disease and different dosing schedules for different types of Candida infections have to be considered. Relevant drug-drug interactions of Caspofungin and Micafungin are minimal. Anidulafungin has no significant drug interactions at all. However, echinocandins are available only for i.v. use. All three agents have an excellent safety profile.
- 189(a) Johns, B. A.; Kawasuji, T.; Weatherhead, J. G.; Taishi, T.; Temelkoff, D. P.; Yoshida, H.; Akiyama, T.; Taoda, Y.; Murai, H.; Kiyama, R.; Fuji, M.; Tanimoto, N.; Jeffrey, J.; Foster, S. A.; Yoshinaga, T.; Seki, T.; Kobayashi, M.; Sato, A.; Johnson, M. N.; Garvey, E. P.; Fujiwara, T. Carbamoyl pyridone HIV-1 integrase inhibitors 3. A diastereomeric approach to chiral nonracemic tricyclic ring systems and the discovery of dolutegravir (S/GSK1349572) and (S/GSK1265744). J. Med. Chem. 2013, 56, 5901– 5916, DOI: 10.1021/jm400645w[ACS Full Text.], [CAS], Google Scholar189ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtVWhurfK&md5=c44c9e62870c2177b07cdd08d22ea600Carbamoyl Pyridone HIV-1 Integrase Inhibitors 3. A Diastereomeric Approach to Chiral Nonracemic Tricyclic Ring Systems and the Discovery of Dolutegravir (S/GSK1349572) and (S/GSK1265744)Johns, Brian A.; Kawasuji, Takashi; Weatherhead, Jason G.; Taishi, Teruhiko; Temelkoff, David P.; Yoshida, Hiroshi; Akiyama, Toshiyuki; Taoda, Yoshiyuki; Murai, Hitoshi; Kiyama, Ryuichi; Fuji, Masahiro; Tanimoto, Norihiko; Jeffrey, Jerry; Foster, Scott A.; Yoshinaga, Tomokazu; Seki, Takahiro; Kobayashi, Masanori; Sato, Akihiko; Johnson, Matthew N.; Garvey, Edward P.; Fujiwara, TamioJournal of Medicinal Chemistry (2013), 56 (14), 5901-5916CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)We report herein the discovery of the human immunodeficiency virus type-1 (HIV-1) integrase inhibitors dolutegravir (S/GSK1349572) (3, III) and S/GSK1265744 (4, IV). These drugs stem from a series of carbamoyl pyridone analogs designed using a two-metal chelation model of the integrase catalytic active site. Structure-activity studies evolved a tricyclic series of carbamoyl pyridines that demonstrated properties indicative of once-daily dosing and superior potency against resistant viral strains. An inherent hemiaminal ring fusion stereocenter within the tricyclic carbamoyl pyridone scaffold led to a crit. substrate controlled diastereoselective synthetic strategy whereby chiral information from small readily available amino alcs. was employed to control relative and abs. stereochem. of the final drug candidates. Modest to extremely high levels of stereochem. control were obsd. depending on ring size and position of the stereocenter. This approach resulted in the discovery of 3 and 4, which are currently in clin. development.(b) Kawasuji, T.; Johns, B. A.; Yoshida, H.; Weatherhead, J. G.; Akiyama, T.; Taishi, T.; Taoda, Y.; Mikamiyama-Iwata, M.; Murai, H.; Kiyama, R.; Fuji, M.; Tanimoto, N.; Yoshinaga, T.; Seki, T.; Kobayashi, M.; Sato, A.; Garvey, E. P.; Fujiwara, T. Carbamoyl pyridone HIV-1 integrase inhibitors. 2. Bi- and tricyclic derivatives result in superior antiviral and pharmacokinetic profiles. J. Med. Chem. 2013, 56, 1124– 1135, DOI: 10.1021/jm301550c[ACS Full Text.], [CAS], Google Scholar189bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXntVeltA%253D%253D&md5=4bfe919f8fdbbc84e346e3f01e084b70Carbamoyl Pyridone HIV-1 Integrase Inhibitors. 2. Bi- and Tricyclic Derivatives Result in Superior Antiviral and Pharmacokinetic ProfilesKawasuji, Takashi; Johns, Brian A.; Yoshida, Hiroshi; Weatherhead, Jason G.; Akiyama, Toshiyuki; Taishi, Teruhiko; Taoda, Yoshiyuki; Mikamiyama-Iwata, Minako; Murai, Hitoshi; Kiyama, Ryuichi; Fuji, Masahiro; Tanimoto, Norihiko; Yoshinaga, Tomokazu; Seki, Takahiro; Kobayashi, Masanori; Sato, Akihiko; Garvey, Edward P.; Fujiwara, TamioJournal of Medicinal Chemistry (2013), 56 (3), 1124-1135CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)This work is a continuation of our initial discovery of a potent monocyclic carbamoyl pyridone human immunodeficiency virus type-1 (HIV-1) integrase inhibitor that displayed favorable antiviral and pharmacokinetic properties. We report herein a series of bicyclic carbamoylpyridone (I; satd. and unsatd. bridge; R = e.g., alkoxyethyl) analogs to address conformational issues from our initial SAR studies. This modification of the core unit succeeded to deliver low nanomolar potency in std. antiviral assays. An addnl. hydroxyl substituent on the bicyclic scaffold provides remarkable improvement of antiviral efficacies against clin. relevant resistant viruses. These findings led to addnl. cyclic tethering of the naked hydroxyl group resulting in tricyclic carbamoyl pyridone inhibitors (II; Y = O, N; n = 0-2; R' = e.g., alkyl, Ac, methanesulfonyl) to address remaining issues and deliver potential clin. candidates. The tricyclic carbamoyl pyridone derivs. described herein served as the immediate leads in mols. to the next generation integrase inhibitor dolutegravir which is currently in late stage clin. evaluation.(c) Kawasuji, T.; Johns, B. A.; Yoshida, H.; Taishi, T.; Taoda, Y.; Murai, H.; Kiyama, R.; Fuji, M.; Yoshinaga, T.; Seki, T.; Kobayashi, M.; Sato, A.; Fujiwara, T. Carbamoyl pyridone HIV-1 integrase inhibitors. 1. Molecular design and establishment of an advanced two-metal binding pharmacophore. J. Med. Chem. 2012, 55, 8735– 8744, DOI: 10.1021/jm3010459[ACS Full Text], [CAS], Google Scholar189chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhtlags7zO&md5=fa751e3f5da1cede1a76cc26c7a15d3aCarbamoyl Pyridone HIV-1 Integrase Inhibitors. 1. Molecular Design and Establishment of an Advanced Two-Metal Binding PharmacophoreKawasuji, Takashi; Johns, Brian A.; Yoshida, Hiroshi; Taishi, Teruhiko; Taoda, Yoshiyuki; Murai, Hitoshi; Kiyama, Ryuichi; Fuji, Masahiro; Yoshinaga, Tomokazu; Seki, Takahiro; Kobayashi, Masanori; Sato, Akihiko; Fujiwara, TamioJournal of Medicinal Chemistry (2012), 55 (20), 8735-8744CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Our group has focused on expanding the scope of a two-metal binding pharmacophore concept to explore HIV-1 integrase inhibitors through medicinal chem. efforts to design novel scaffolds which allow for improvement of pharmacokinetic (PK) and resistance profiles. A novel chelating scaffold was rationally designed to effectively coordinate two magnesium cofactors and to extend an arom. group into an optimal hydrophobic pharmacophore space. The new chemotype, consisting of a carbamoyl pyridone core unit, shows high inhibitory potency in both enzymic and antiviral assay formats with low nM IC50 and encouraging potency shift effects in the presence of relevant serum proteins. The new inhibitor design displayed a remarkable PK profile suggestive of once daily dosing without the need for a PK booster as demonstrated by robust drug concns. at 24 h after oral dosing in rats, dogs, and cynomolgus monkeys.
- 190(a) Tsiang, M.; Jones, G. S.; Goldsmith, J.; Mulato, A.; Hansen, D.; Kan, E.; Tsai, L.; Bam, R. A.; Stepan, G.; Stray, K. M.; Niedziela-Majka, A.; Yant, S. R.; Yu, H.; Kukolj, G.; Cihlar, T.; Lazerwith, S. E.; White, K. L.; Jin, H. Antiviral activity of bictegravir (GS-9883), a novel potent HIV-1 integrase strand transfer inhibitor with an improved resistance profile. Antimicrob. Agents Chemother. 2016, 60, 7086– 7097, DOI: 10.1128/AAC.01474-16[Crossref], [PubMed], [CAS], Google Scholar.190ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXitlWjt78%253D&md5=87a180a313ffaa8b03201b06a8c875ffAntiviral activity of bictegravir (GS-9883), a novel potent HIV-1 integrase strand transfer inhibitor with an improved resistance profileTsiang, Manuel; Jones, Gregg S.; Goldsmith, Joshua; Mulato, Andrew; Hansen, Derek; Kan, Elaine; Tsai, Luong; Bam, Rujuta A.; Stepan, George; Stray, Kirsten M.; Niedziela-Majka, Anita; Yant, Stephen R.; Yu, Helen; Kukolj, George; Cihlar, Tomas; Lazerwith, Scott E.; White, Kirsten L.; Jin, HaolunAntimicrobial Agents and Chemotherapy (2016), 60 (12), 7086-7097CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)Bictegravir (BIC; GS-9883), a novel, potent, once-daily, unboosted inhibitor of HIV-1 integrase (IN), specifically targets IN strand transfer activity (50% inhibitory concn. [IC50] of 7.5 ± 0.3 nM) and HIV-1 integration in cells. BIC exhibits potent and selective in vitro antiretroviral activity in both T-cell lines and primary human T lymphocytes, with 50% effective concns. ranging from 1.5 to 2.4 nM and selectivity indexes up to 8,700 relative to cytotoxicity. BIC exhibits synergistic in vitro antiviral effects in pairwise combinations with tenofovir alafenamide, emtricitabine, or darunavir and maintains potent antiviral activity against HIV-1 variants resistant to other classes of antiretrovirals. BIC displayed an in vitro resistance profile that was markedly improved compared to the integrase strand transfer inhibitors (INSTIs) raltegravir (RAL) and elvitegravir (EVG), and comparable to that of dolutegravir (DTG), against nine INSTI-resistant site-directed HIV-1 mutants. BIC displayed statistically improved antiviral activity relative to EVG, RAL, and DTG against a panel of 47 patient-derived HIV-1 isolates with highlevel INSTI resistance; 13 of 47 tested isolates exhibited >2-fold lower resistance to BIC than DTG. In dose-escalation expts. conducted in vitro, BIC and DTG exhibited higher barriers to resistance than EVG, selecting for HIV-1 variants with reduced phenotypic susceptibility at days 71, 87, and 20, resp. A recombinant virus with the BIC-selected M50I/R263K dual mutations in IN exhibited only 2.8-fold reduced susceptibility to BIC compared to wild-type virus. All BIC-selected variants exhibited low to intermediate levels of cross-resistance to RAL, DTG, and EVG (<8-fold) but remained susceptible to other classes of antiretrovirals. A high barrier to in vitro resistance emergence for both BIC and DTG was also obsd. in viral breakthrough studies in the presence of const. clin. relevant drug concns. The overall virol. profile of BIC supports its ongoing clin. investigation in combination with other antiretroviral agents for both treatment-naive and -experienced HIV-infected patients.(b) Lazerwith, S. E.; Cai, R.; Chen, X.; Chin, G.; Desai, M. C.; Eng, S.; Jacques, R.; Ji, M.; Jones, G.; Martin, H.; McMahon, C.; Mish, M.; Morganelli, P.; Mwangi, J.; Pyun, H.; Schmitz, U.; Stepan, G.; Szwarcberg, J.; Tang, J.; Tsiang, M.; Wang, J.; Wang, K.; White, K.; Wiser, L.; Zack, J.; Jin, H. Discovery of bictegravir (GS-9883), a novel, unboosted, once-daily HIV-1 integrase strand transfer inhibitor (INSTI) with improved pharmacokinetics and in vitro resistance profile. ASM Microbe: Boston, MA, 2016.
- 191Deeks, E. D. Bictegravir/emtricitabine/tenofovir alafenamide: a review in HIV-1 infection. Drugs 2018, 78, 1817– 1828, DOI: 10.1007/s40265-018-1010-7[Crossref], [PubMed], [CAS], Google Scholar191https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXit1GgtbbK&md5=ffec7739b3a4dda20f945a8dd3539422Bictegravir/Emtricitabine/Tenofovir Alafenamide: A Review in HIV-1 InfectionDeeks, Emma D.Drugs (2018), 78 (17), 1817-1828CODEN: DRUGAY; ISSN:0012-6667. (Springer International Publishing AG)Bictegravir is a new integrase strand transfer inhibitor (INSTI) with a high genetic barrier to the development of HIV-1 resistance. The drug is co-formulated with the nucleos(t)ide reverse transcriptase inhibitors emtricitabine and tenofovir alafenamide (AF) in a single-tablet regimen (STR) for the once-daily treatment of HIV-1 infection in adults (bictegravir/emtricitabine/tenofovir AF; Biktarvy). In phase 3 trials, bictegravir/emtricitabine/tenofovir AF was noninferior to dolutegravir-based therapy (dolutegravir/abacavir/lamivudine or dolutegravir plus emtricitabine/tenofovir AF) in establishing virol. suppression in treatment-naive adults through 96 wk' treatment and, similarly, was noninferior to ongoing dolutegravir/abacavir/lamivudine or boosted elvitegravir- or protease inhibitor (PI)-based therapy in preventing virol. rebound over 48 wk in treatment-experienced patients. No resistance emerged to any of the antiretrovirals in the STR. Bictegravir/emtricitabine/tenofovir AF is generally well tolerated, requires no prior HLA-B*5701 testing (making it more suitable for 'rapid start' treatment), fulfils the antiretroviral regimen requirement for patients with hepatitis B virus (HBV) co-infection (i.e. contains tenofovir AF and emtricitabine, both of which are active against HBV) and can be used in renally impaired patients with creatinine clearance (CRCL) ≥ 30 mL/min. Thus, although cost-effectiveness analyses would be beneficial, current data indicate that bictegravir/emtricitabine/tenofovir AF is a convenient initial and subsequent treatment option for adults with HIV-1 infection, including those co-infected with HBV, and provides the first non-pharmacol. boosted, INSTI-based, triple-combination STR suitable for patients with CRCL 30-50 mL/min.
- 192(a) Wu, Y.-J.; Guernon, J.; Rajamani, R.; Toyn, J. H.; Ahlijanian, M. K.; Albright, C. F.; Muckelbauer, J.; Chang, C.; Camac, D.; Macor, J. E.; Thompson, L. A. Discovery of furo[2,3-d][1,3]thiazinamines as β-amyloid cleaving enzyme-1 (BACE1) inhibitors. Bioorg. Med. Chem. Lett. 2016, 26, 5729– 5731, DOI: 10.1016/j.bmcl.2016.10.055[Crossref], [PubMed], [CAS], Google Scholar.192ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhsl2itr7F&md5=95eacab8d71d6a4ab35e1b436029b829Discovery of furo[2,3-d][1,3]thiazinamines as beta amyloid cleaving enzyme-1 (BACE1) inhibitorsWu, Yong-Jin; Guernon, Jason; Rajamani, Ramkumar; Toyn, Jeremy H.; Ahlijanian, Michael K.; Albright, Charles F.; Muckelbauer, Jodi; Chang, ChiehYing; Camac, Dan; Macor, John E.; Thompson, Lorin A.Bioorganic & Medicinal Chemistry Letters (2016), 26 (23), 5729-5731CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)This Letter describes the synthesis and structure-activity relationships of a series of furo[2,3-d][1,3]thiazinamine BACE1 inhibitors. The co-crystal structure of a representative thiazinamine I bound with the BACE1 active site displayed a binding mode driven by interactions with the catalytic aspartate dyad and engagement of the biaryl amide toward the S1 and S3 pockets. This work indicates that furo[2,3-d]thiazine can serve as a viable bioisostere of the known furo[3,4-d]thiazine.(b) Wu, Y.-J.; Guernon, J.; Park, H.; Thompson, L. A. Expedient synthesis of fluoro[2,3-d[1,3]thiazinamines and pyrano-[2,3-d][1,3]thiazinamines from enones and thiourea. J. Org. Chem. 2016, 81, 3386– 3390, DOI: 10.1021/acs.joc.5b02705[ACS Full Text], [CAS], Google Scholar192bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XksFGrsro%253D&md5=4cc318a4bd852be9795f0f41e464c1dfExpedient Synthesis of Furo[2,3-d][1,3]thiazinamines and Pyrano[2,3-d][1,3]thiazinamines from Enones and ThioureaWu, Yong-Jin; Guernon, Jason; Park, Hyunsoo; Thompson, Lorin A.Journal of Organic Chemistry (2016), 81 (8), 3386-3390CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)Michael addn. of thiourea to enones with subsequent intramol. aminal ether formation provided easy access to furo[2,3-d]thiazinamines and pyrano[2,3-d][1,3]thiazin-2-amines. These amines served as versatile intermediates to a variety of beta-amyloid cleaving enzyme-1 (BACE1) inhibitors.
- 193Futamura, A.; Suzuki, R.; Tamura, Y.; Kawamoto, H.; Ohmichi, M.; Hino, N.; Tokumaru, Y.; Kirinuki, S.; Hiyoshi, T.; Aoki, T.; Kambe, D.; Nozawa, D. Discovery of ORN0829, a potent dual orexin 1/2 receptor antagonist for the treatment of insomnia. Bioorg. Med. Chem. 2020, 28, 115489, DOI: 10.1016/j.bmc.2020.115489[Crossref], [PubMed], [CAS], Google Scholar193https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtVOmu73J&md5=a48f3baab0761535af73ffa790b9835cDiscovery of ORN0829, a potent dual orexin 1/2 receptor antagonist for the treatment of insomniaFutamura, Aya; Suzuki, Ryo; Tamura, Yunoshin; Kawamoto, Hiroshi; Ohmichi, Mari; Hino, Noriko; Tokumaru, Yuichi; Kirinuki, Sora; Hiyoshi, Tetsuaki; Aoki, Takeshi; Kambe, Daiji; Nozawa, DaiBioorganic & Medicinal Chemistry (2020), 28 (13), 115489CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)Here, the authors present the design, synthesis, and SAR of dual orexin I and II receptor antagonists, which were optimized by balancing the antagonistic activity for orexin receptors and lipophilicity. Based on the prototype compd. I, ring construction and the insertion of an addnl. heteroatom into the resulting ring led to the discovery of orexin I and II receptor antagonists, which were 3-benzoyl-1,3-oxazinane derivs. Within these derivs., III enabled a high dual orexin receptor antagonistic activity and a low lipophilicity. Compd. III exhibited potent sleep-promoting effects at a po dose of 1 mg/kg in a rat polysomnogram study, and optimal PK properties with a rapid Tmax and short half-lives in rats and dogs were obsd., indicating a predicted human half-life of 0.9-2.0 h. Thus, III(ORN0829; study code name, TS-142) was selected as a viable candidate and is currently in clin. development for the treatment of insomnia.
- 194(a) Miller, T. W.; Goegelman, R. T.; Weston, R. G.; Putter, I.; Wolf, F. J. Cephamycins, a new family of β-lactam antibiotics. II. Isolation and chemical characterization. Antimicrob. Agents Chemother. 1972, 2, 132– 135, DOI: 10.1128/AAC.2.3.132[Crossref], [PubMed], [CAS], Google Scholar.194ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE3sXjvFOgtg%253D%253D&md5=5be8b99ea02792cdff1649ae81936011Cephamycins, a new family of β-lactam antibiotics. II. Isolation and chemical characterizationMiller, T. W.; Goegelman, R. T.; Weston, R. G.; Putter, I.; Wolf, F. J.Antimicrobial Agents and Chemotherapy (1972), 2 (3), 132-5CODEN: AMACCQ; ISSN:0066-4804.Fermentation broths from cultures of various microorganisms were used for the sepn. of cephamycins A, B, and C. The broths were acidified and absorbed onto a column of Amberlite XAD-2. After elution with 60% aq. methanol, the eluate was concd., adjusted to pH 3.5 with NH4OH, and absorbed onto a column of Amberlite IRZ-68 (Cl-). This was eluted with 1M NaNO3 + 0.1M NaOAc at pH 7.5. The eluate was adjusted to pH 3 and absorbed onto Amberlite XAD-2, eluted with 25% aq. acetone, and concd. under reduced pressure. The material was then sepd. by DEAE-Sephadex A-25 resin using const. buffer elution with 0.5M NH4Br + 0.05M AcOH. The sepd. cephamycins A and B were desalted using Amberlite XAD-2, and lyophilized. Cephamycin C was prepd. by a different process in which the fermentation broth was passed through a column of Dowex 1-X2 (Cl-) and eluted with 5% aq. NaCl soln. The high activity fractions were acidified to pH 2 with HCl, adsorbed onto Dowex 50-X2 (H+), and eluted with 2% aq. pyridine. The eluate was neutralized with NaOH soln. and concd. under reduced pressure. This was absorbed onto a column of Dowex 1-X2 (Cl-) equilibrated with 0.1M pyridine-HCl buffer at pH 5, and the column was developed with the same buffer. The high activity fractions were adjusted to pH 8 and dried. This material was desalted by chromatog. on Biogel-P2. The 3 cephamycins were analyzed to det. their empirical formulas, mol. wts., uv spectra, amino acid analysis, and CD. Cephamycin C was identical to antibiotic 4 reported by Nagarajan, R., et al. (1971), but cephamycins A and B appeared to be new compds.(b) Stapley, E. O.; Birnbaum, J.; Miller, A. K.; Wallick, H.; Hendlin, D.; Woodruff, H. B. Cefoxitin and cephamycins: microbiological studies. Clin. Infect. Dis. 1979, 1, 73– 87, DOI: 10.1093/clinids/1.1.73
- 195Brites, L. M.; Oliveira, L. M.; Barboza, M. Kinetic study on cephamycin C degradation. Appl. Biochem. Appl. Biochem. Biotechnol. 2013, 171, 2121– 2128, DOI: 10.1007/s12010-013-0502-x[Crossref], [PubMed], [CAS], Google Scholar195https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVCitrvO&md5=c00dc6d568997c8967e68fcee4350953Kinetic Study on Cephamycin C DegradationBrites, Luciana M.; Oliveira, Liliane M.; Barboza, MarleiApplied Biochemistry and Biotechnology (2013), 171 (8), 2121-2128CODEN: ABIBDL; ISSN:0273-2289. (Springer)Cephamycin C (CepC) is a β-lactam antibiotic that belongs to the cephalosporin class of drugs. This compd. stands out from other cephalosporins for its greater resistance to β-lactamases, which are enzymes produced by pathogenic microorganisms that present a major mechanism of bacterial resistance to β-lactam antibiotics. Cephamycin C is produced by the bacterium Streptomyces clavuligerus. Knowledge about the stability of the compd. under different values of pH is important for the development of the process of prodn., extn., and purifn. aimed at obtaining higher yields. Therefore, the stability of cephamycin C under different pH levels (2.2, 6.0, 7.0, 7.6, and 8.7) at 20 °C was evaluated in this study. Ultrafiltered broth from batch fermns. of S. clavuligerus was used in the trials. The results indicated that cephamycin C is a more stable compd. than other β-lactam compds. such as penicillin and clavulanic acid. A higher degrdn. rate was obsd. at very acidic or basic pH levels, while this rate was lower at quasi-neutral pH levels. After 100 h of trial, the initial CepC showed 46 % degrdn. at pH 2.2, 71 % degrdn. at pH 8.7, and varied from 15 to 20 % at quasi-neutral pH levels.
- 196(a) Hagmann, W. K.; Thompson, K. R.; Shah, S. K.; Finke, P. E.; Ashe, B. M.; Weston, H.; Maycock, A. L.; Doherty, J. B. The effect of N-acyl substituents on the stability of monocyclic β-lactam inhibitors of human leukocyte elastase. Bioorg. Med. Chem. Lett. 1992, 2, 681– 684, DOI: 10.1016/S0960-894X(00)80390-X[Crossref], [CAS], Google Scholar.196ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3sXkt1ensLk%253D&md5=ce657004b4e19cdb99073afa3c197242The effect of N-acyl substituents on the stability of monocyclic β-lactam inhibitors of human leukocyte elastaseHagmann, William K.; Thompson, Kevan R.; Shah, Shrenik K.; Finke, Paul E.; Ashe, Bonnie M.; Weston, Hazel; Maycock, Alan L.; Doherty, James B.Bioorganic & Medicinal Chemistry Letters (1992), 2 (7), 681-4CODEN: BMCLE8; ISSN:0960-894X.Substituted monocyclic β-lactams have recently been reported as inhibitors of human leukocyte elastase (HLE). Simple N-acetyl-2-azetidinone lead structures were found to undergo N-deacylation as well as β-lactam ring opening. The development of the N-carbamoyl-2-azetidinone nucleus was crucial to the stability of these compds. for effective oral bioavailability.(b) Finke, P. E.; Shah, S. K.; Fletcher, D. S.; Ashe, B. M.; Brause, K. A.; Chandler, G. O.; Dellea, P. S.; Hand, K. M.; Maycock, A. L. Orally active β-lactam inhibitors of human leukocyte elastase. 3. Stereospecific synthesis and structure-activity relationships for 3,3-dialkylazetidin-2-ones. J. Med. Chem. 1995, 38, 2449– 2462, DOI: 10.1021/jm00013a021[ACS Full Text.], [CAS], Google Scholar196bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXmtVyhsbY%253D&md5=a413402d09b5abfa9fad9b7301fe8a02Orally Active β-Lactam Inhibitors of Human Leukocyte Elastase. 3. Stereospecific Synthesis and Structure-Activity Relationships for 3,3-Dialkylazetidin-2-onesFinke, Paul E.; Shah, Shrenik K.; Fletcher, Daniel S.; Ashe, Bonnie M.; Brause, Karen A.; Chandler, Gilbert O.; Dellea, Pam S.; Hand, Karen M.; Maycock, Alan L.; et al.Journal of Medicinal Chemistry (1995), 38 (13), 2449-62CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The stereospecific synthesis of several 4-[(4-carboxyphenyl)oxy]-3,3-dialkyl-1-[[(1-phenylalkyl)amino]carbonyl]azetidin-2-ones I [R1 = R2 = H, Rβ = H, Me, Et, n-Pr, etc., Rα = Et, Me, n-Pr, allyl, RβRα = (CH2)4; R1 = Me, H, Et, n-Pr, R2 = H, Me, Et, Rβ = Me, n-Pr, Rα = Et] is described in which the C-3 alkyl groups were varied from Me to Bu as well as allyl, benzyl and methoxymethyl. The structure-activity relations for these compds. are discussed in terms of the hydrolytic stability of the β-lactam ring, their in vitro inhibitory potency for human leukocyte elastase (HLE), and their in vivo oral efficacy in an HLE-mediated hamster lung hemorrhage assay. Further alkyl substitution on the benzylic urea moiety, esp. in the R configuration, afforded enhanced HLE inhibition and in vivo efficacy. The stereochem. assignments for (3R,4S)-4-[(4-carboxyphenyl)oxy]-3-ethyl-3-methyl-1-[[((R)-1-phenylpropyl)amino]carbonyl]azetidin-2-one (kobs/[I] = 91 000 M-1 s-1) were confirmed with an X-ray structure detn., which was also utilized to develop an HLE inhibition model.(c) Doherty, J. B.; Shah, S. K.; Finke, P. E.; Dorn, C. P.; Hagmann, W. K.; Hale, J. J.; Kissinger, A. L.; Thompson, K. R.; Brause, K.; Chandler, G. O. Chemical, biochemical, pharmacokinetic, and biological properties of L-680,833: a potent, orally active monocyclic β-lactam inhibitor of human polymorphonuclear leukocyte elastase. Proc. Natl. Acad. Sci. U. S. A. 1993, 90, 8727– 8731, DOI: 10.1073/pnas.90.18.8727[Crossref], [PubMed], [CAS], Google Scholar.196chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2cXjslA%253D&md5=17ff24f09bc6b8cfa04b07dd2cb0b4b3Chemical, biochemical, pharmacokinetic, and biological properties of L-680,833: A potent, orally active monocyclic β-lactam inhibitor of human polymorphonuclear leukocyte elastaseDoherty, James B.; Shah, Shrenik K.; Finke, Paul E.; Dorn, Conrad P., Jr.; Hagmann, William K.; Hale, Jeffrey J.; Kissinger, Amy L.; Thompson, Kevan R.; Brause, Karen; et al.Proceedings of the National Academy of Sciences of the United States of America (1993), 90 (18), 8727-31CODEN: PNASA6; ISSN:0027-8424.A series of potent and highly selective time-dependent monocyclic β-lactam inhibitors of human polymorphonuclear leukocyte elastase (PMNE, EC 3.4.21.37) is described. The intrinsic potency of these compds., as exemplified by L-680,833 (kinactivation/Ki of 622,000 M-1-s-1), is reflected at the cellular level where it inhibits generation of the specific N-terminal cleavage product Aα-(1-21) from the Aα chain of fibrinogen by enzyme released from isolated polymorphonuclear leukocytes stimulated with fMet-Leu-Phe with an IC50 of 0.06 μM. The inhibitory activity of L-680,833 is also apparent in whole blood stimulated with A23187, where it inhibits formation of Aα-(1-21) and PMNE-α1-proteinase inhibitor complex formation with IC50 values of 9 μM. Pharmacokinetic studies indicate that after oral dosing L-680,833 is bioavailable in rats and rhesus monkeys. This oral bioavailability is reflected by the inhibition (i) of tissue damage elicited in hamster lungs by intratracheal instillation of human PMNE and (ii) enzyme released from human PMN stimulated after their transfer into the pleural cavity of mice. The properties of L-680,833 allow it to effectively supplement the activity of natural inhibitors of PMNE in vivo, suggesting that this type of low-mol.-wt. synthetic inhibitor could have therapeutic value in diseases where PMNE damages tissue.(d) Vincent, S. H.; Painter, S. K.; Luffer-Atlas, D.; Karanam, B. V.; McGowan, E.; Cioffe, C.; Doss, G.; Chiu, S. Orally active inhibitors of human leukocyte elastase. II. Disposition of L-694,458 in rats and rhesus monkeys. Drug Metab. Dispos. 1997, 25, 932– 939[PubMed], [CAS], Google Scholar196dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXlsVGmsr0%253D&md5=8238bfaaa41c61c88424fff290dfec31Orally active inhibitors of human leukocyte elastase. II. Disposition of L-694,458 in rats and rhesus monkeysVincent, Styliani H.; Painter, Susan K.; Luffer-Atlas, Debra; Karanam, Bindhu V.; Mcgowan, E.; Cloffe, Chris; Doss, George; Chlu, Shuet-Hing L.Drug Metabolism and Disposition (1997), 25 (8), 932-939CODEN: DMDSAI; ISSN:0090-9556. (Williams & Wilkins)The disposition of L-694,458, a potent monocyclic β-lactam inhibitor of human leukocyte elastase, was studied in male Sprague-Dawley rats and rhesus monkeys. After i.v. dosing, L-694,458 exhibited similar pharmacokinetic parameters in rats and rhesus monkeys. The mean values for its plasma clearance, terminal half-life, and vol. of distribution at steady state were 27 mL/min/kg, 1.8 h, and 4.0 L/kg in rats and 34 mL/min/kg, 2.3 h, and 5 L/kg in rhesus monkeys. The bioavailability of a 10 mg/kg oral dose was higher in rats (65%) than in rhesus monkeys (39%). In both species, concns. of L-694,458 in plasma increased more than proportionally when the oral dose was increased from 10 mg/kg to 40 mg/kg. In monkeys a protracted plasma concn.-time profile was obsd. at 40 mg/kg, characterized by a delayed Tmax (8-24 h) and a long terminal half-life (6 h). [3H]L-694,458 was well absorbed after oral dosing to rats at 10 mg/kg, as indicated by the high recovery of radioactivity in bile (83%) and urine (6%) of bile duct-cannulated rats. Only ∼5% or less of the radioactivity in bile, urine, and feces was a result of intact L-694,458, indicating that the compd. was being eliminated by metab., followed by excretion of the metabolites in feces, via bile. Demethylation of the methylenedioxyphenyl group resulting in the catechol was the primary metabolic pathway in human and rhesus monkey liver microsomes. In rat liver microsomes, the major metabolite was the N-oxide of the methyl-substituted piperazine nitrogen. In rats dosed i.v. and orally with [3H]L-694,458, concns. of radioactivity were highest in the lung (the primary target tissue), adrenals, and liver. L-694,458 was unstable in rat blood and plasma, degrading via a pathway believed to be catalyzed by B-esterases and to involve cleavage of the β-lactam ring and loss of the methylpiperazine phenoxy group. In vitro studies indicated that in human liver, L-694,458 was metabolized by CYP3A and CYP2C isoenzymes, and in both monkey and human liver microsomes the compd. acted as an inhibitor of testosterone 6β-hydroxylation.
- 197Halas, C. J. Eszopiclone. Am. J. Health-Syst. Pharm. 2006, 63, 41– 48, DOI: 10.2146/ajhp050357[Crossref], [PubMed], [CAS], Google Scholar197https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XntVCmuw%253D%253D&md5=9845c47e5baec4f9a8d75b0e49cbba1fEszopicloneHalas, Cynthia J.American Journal of Health-System Pharmacy (2006), 63 (1), 41-48CODEN: AHSPEK; ISSN:1079-2082. (American Society of Health-System Pharmacists)A review. Purpose. The pharmacol., pharmacokinetics, indications, clin. efficacy, adverse effects, drug interactions, dosing, and administration of eszopiclone are discussed. Summary. The pharmacol. of eszopiclone is not well understood. Eszopiclone is the S-isomer of racemic zopiclone. The relative bioavailability of oral racemic zopiclone is about 80%. Eszopiclone is rapidly absorbed after oral administration, with peak serum concns. ranging from 1 to 1.3 h. The efficacy of eszopiclone has been evaluated in healthy adults, including elderly patients, for the treatment of transient and chronic insomnia. Compared with placebo, eszopiclone has been shown to considerably reduce sleep induction and improve sleep maintenance, duration, quality, and depth, as well as next-day functioning. The most common adverse effects reported are unpleasant taste, headache, and dry mouth. Dosing should be individualized, and the lowest ED should be used to minimize the risk of adverse events. The recommended starting dosage for nonelderly patients is 2 mg immediately before bedtime, with adjustment to 3 mg if clin. indicated. Dosage adjustment is necessary in patients with severe hepatic disease and in those receiving concomitant potent cytochrome P 450 isoenzyme 3A4 inhibitors. No dosage adjustment is required for patients with renal dysfunction. The cost of eszopiclone is $3.70 per tablet for all dosage strengths (1-, 2-, and 3-mg tablets). Conclusion. Its favorable adverse-effect profile and approved labeling for the treatment of chronic insomnia makes eszopiclone a viable alternative for insomnia treatment. Published data are limited, however, and more clin. trials, including comparator studies, are needed to further evaluate the use of this drug.
- 198(a) Shelton, J.; Lu, X.; Hollenbaugh, J. A.; Cho, J. H.; Amblard, F.; Schinazi, R. F. Metabolism, biochemical actions, and chemical synthesis of anticancer nucleosides, nucleotides, and base analogues. Chem. Rev. 2016, 116, 14379– 14455, DOI: 10.1021/acs.chemrev.6b00209[ACS Full Text.], [CAS], Google Scholar198ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhvFWgtL3J&md5=84cbe9e13e6bdaff88a9d49caea2f99aMetabolism, Biochemical Actions, and Chemical Synthesis of Anticancer Nucleosides, Nucleotides, and Base AnalogsShelton, Jadd; Lu, Xiao; Hollenbaugh, Joseph A.; Cho, Jong Hyun; Amblard, Franck; Schinazi, Raymond F.Chemical Reviews (Washington, DC, United States) (2016), 116 (23), 14379-14455CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. Nucleoside, nucleotide, and base analogs have been in the clinic for decades to treat both viral pathogens and neoplasms. More than 20% of patients on anticancer chemotherapy have been treated with one or more of these analogs. This review focuses on the chem. synthesis and biol. of anticancer nucleoside, nucleotide, and base analogs that are FDA-approved and in clin. development since 2000. The authors highlight the cellular biol. and clin. biol. of analogs, drug resistance mechanisms, and compd. specificity towards different cancer types. Furthermore, the authors explore analog syntheses as well as improved and scale-up syntheses. The authors conclude with a discussion on what might lie ahead for medicinal chemists, biologists, and physicians as they try to improve analog efficacy through prodrug strategies and drug combinations.(b) Seley-Radtke, K.; Yates, M. K. The evolution of nucleoside analogue antivirals: a review for chemists and non-chemists. Part I: Early structural modifications to the nucleoside scaffold. Antiviral Res. 2018, 154, 66– 86, DOI: 10.1016/j.antiviral.2018.04.004[Crossref], [PubMed], [CAS], Google Scholar.198bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXnslOntrc%253D&md5=ccd9ad86ef8a1baf078e21747edef73dThe evolution of nucleoside analogue antivirals: A review for chemists and non-chemists. Part 1: Early structural modifications to the nucleoside scaffoldSeley-Radtke, Katherine L.; Yates, Mary K.Antiviral Research (2018), 154 (), 66-86CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)A review. This is the first of two invited articles reviewing the development of nucleoside-analog antiviral drugs, written for a target audience of virologists and other non-chemists, as well as chemists who may not be familiar with the field. Rather than providing a simple chronol. account, we have examd. and attempted to explain the thought processes, advances in synthetic chem. and lessons learned from antiviral testing that led to a few mols. being moved forward to eventual approval for human therapies, while others were discarded. The present paper focuses on early, relatively simplistic changes made to the nucleoside scaffold, beginning with modifications of the nucleoside sugars of Ara-C and other arabinose-derived nucleoside analogs in the 1960's. A future paper will review more recent developments, focusing esp. on more complex modifications, particularly those involving multiple changes to the nucleoside scaffold. We hope that these articles will help virologists and others outside the field of medicinal chem. to understand why certain drugs were successfully developed, while the majority of candidate compds. encountered barriers due to low-yielding synthetic routes, toxicity or other problems that led to their abandonment.(c) Seley-Radtke, K.; Yates, M. K. The evolution of nucleoside analogue antivirals: a review for chemists and non-chemists. Part II: Complex modifications to the nucleoside scaffold. Antiviral Res. 2019, 162, 5– 21, DOI: 10.1016/j.antiviral.2018.11.016[Crossref], [PubMed], [CAS], Google Scholar.198chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisFSntrzL&md5=26d398d67fa3ae4c54318057eb18b35fThe evolution of antiviral nucleoside analogues: A review for chemists and non-chemists. Part II: Complex modifications to the nucleoside scaffoldYates, Mary K.; Seley-Radtke, Katherine L.Antiviral Research (2019), 162 (), 5-21CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)This is the second of two invited articles reviewing the development of nucleoside analog antiviral drugs, written for a target audience of virologists and other non-chemists, as well as chemists who may not be familiar with the field. As with the first paper, rather than providing a chronol. account, we have chosen to examine particular examples of structural modifications made to nucleoside analogs that have proven fruitful as various antiviral, anticancer, and other therapeutics. The first review covered the more common, and in most cases, single modifications to the sugar and base moieties of the nucleoside scaffold. This paper focuses on more recent developments, esp. nucleoside analogs that contain more than one modification to the nucleoside scaffold. We hope that these two articles will provide an informative historical perspective of some of the successfully designed analogs, as well as many candidate compds. that encountered obstacles.(d) Li, G.; Yue, T.; Zhang, P.; Gu, W.; Gao, L.-J.; Tan, L. Drug discovery of nucleos(t)ide antiviral agents: dedicated to Prof. Dr. Erik De Clercq on occasion of his 80th birthday. Molecules 2021, 26, 923, DOI: 10.3390/molecules26040923[Crossref], [PubMed], [CAS], Google Scholar.198dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXltFWktr4%253D&md5=c3fca1064f90ee94443ebd7b1e93f25eDrug discovery of nucleos(t)ide antiviral agents: dedicated to Prof. Dr. Erik De Clercq on occasion of his 80th birthdayLi, Guangdi; Yue, Tingting; Zhang, Pan; Gu, Weijie; Gao, Ling-Jie; Tan, LiMolecules (2021), 26 (4), 923CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)A review. Nucleoside and nucleotide analogs are essential antivirals in the treatment of infectious diseases such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), herpes simplex virus (HSV), varicella-zoster virus (VZV), and human cytomegalovirus (HCMV). To celebrate the 80th birthday of Prof. Dr. Erik De Clercq on 28 March 2021, this review provides an overview of his contributions to eight approved nucleos(t)ide drugs: (i) three adenosine nucleotide analogs, namely tenofovir disoproxil fumarate (Viread) and tenofovir alafenamide (Vemlidy) against HIV and HBV infections and adefovir dipivoxil (Hepsera) against HBV infections; (ii) two thymidine nucleoside analogs, namely brivudine (Zostex) against HSV-1 and VZV infections and stavudine (Zerit) against HIV infections; (iii) two guanosine analogs, namely valacyclovir (Valtrex, Zelitrex) against HSV and VZV and rabacfosadine (Tanovea-CA1) for the treatment of lymphoma in dogs; and (iv) one cytidine nucleotide analog, namely cidofovir (Vistide) for the treatment of HCMV retinitis in AIDS patients. Although adefovir dipivoxil, stavudine, and cidofovir are virtually discontinued for clin. use, tenofovir disoproxil fumarate and tenofovir alafenamide remain the most important antivirals against HIV and HBV infections worldwide. Overall, the broad-spectrum antiviral potential of nucleos(t)ide analogs supports their development to treat or prevent current and emerging infectious diseases worldwide.(e) Guinan, M.; Benckendorff, C.; Smith, M.; Miller, G. J. Recent advances in the chemical synthesis and evaluation of anticancer nucleoside analogues. Molecules 2020, 25, 2050, DOI: 10.3390/molecules25092050[Crossref], [CAS], Google Scholar198ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtFWgurvK&md5=5173b380500853de9410bc6beaf6d9b3Recent advances in the chemical synthesis and evaluation of anticancer nucleoside analoguesGuinan, Mieke; Benckendorff, Caecilie; Smith, Mark; Miller, Gavin J.Molecules (2020), 25 (9), 2050CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)A review. Nucleoside analogs have proven to be highly successful chemotherapeutic agents in the treatment of a wide variety of cancers. Several such compds., including gemcitabine and cytarabine, are the go-to option in first-line treatments. However, these materials do have limitations and the development of next generation compds. remains a topic of significant interest and necessity. Herein, we discuss recent advances in the chem. synthesis and biol. evaluation of nucleoside analogs as potential anticancer agents. Focus is paid to 4'-heteroatom substitution of the furanose oxygen, 2'-, 3'-, 4'- and 5'-position ring modifications and the development of new prodrug strategies for these materials.
- 199(a) Garrett, E. R.; Seydel, J. K.; Sharpen, A. J. The acid-catalyzed solvolysis of pyrimidine nucleosides. J. Org. Chem. 1966, 31, 2219– 2227, DOI: 10.1021/jo01345a033[ACS Full Text.], [CAS], Google Scholar199ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF28XksVOqurk%253D&md5=dc0e63159bfb8a7b925ba3a994504ea7The acid-catalyzed solvolysis of pyrimidine nucleosidesGarrett, Edward R.; Seydel, Joachim K.; Sharpen, Alan J.Journal of Organic Chemistry (1966), 31 (7), 2219-27CODEN: JOCEAH; ISSN:0022-3263.The kinetics of acid-catalyzed solvolysis of various pyrimidine nucleosides were studied at various temps. and specific acid catalysis was established for all compds. except 5-hydroxyuridine which exhibited pH-independent solvolysis. Acid stability is markedly affected by the no. of OH groups in the sugar ring with complete hydroxylation of the sugar preventing degradation under the conditions used. The stereochemistry of the 3'-OH exerted a significant effect on the rate of solvolysis of 2'-deoxy-D-erythro-pentosides. Both electroneg. and electropos. substituents in the 5 position of the pyrimidine ring increased the rate of acid-catalyzed solvolysis relative to the unsubstituted 2'-deoxyuridine. The nucleosides solvolyzed at the glycoside link yielding the corresponding uracil and degraded sugar as products. An exception was 5-iodouridine which was transformed to uridine. The mechanism of glycosylamine hydrolysis in acid media is not clear; however, the substituent effects observed can be explained in terms of reactivity of various proposed intermediates in the degradation sequence.(b) Zoltewicz, J. A.; Clark, D. F.; Sharpless, T. W.; Grahe, G. Kinetics and mechanism of the acid-catalyzed hydrolysis of some purine nucleosides. J. Am. Chem. Soc. 1970, 92, 1741– 1750, DOI: 10.1021/ja00709a055[ACS Full Text.], [CAS], Google Scholar199bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE3cXhtlejtbY%253D&md5=c0b19917b35108cfb6cc95d2951d90bbKinetics and mechanism of the acid-catalyzed hydrolysis of some purine nucleosidesZoltewicz, John A.; Clark, D. Fred; Sharpless, Thomas W.; Grahe, GerwaltJournal of the American Chemical Society (1970), 92 (6), 1741-50CODEN: JACSAT; ISSN:0002-7863.Rates of acid-catalyzed hydrolysis were obtained by spectrophotometric methods for the natural nucleosides guanosine (Guo), 2'-deoxyguanosine (dGuo), and 2'-deoxyadenosine (dAdo) and for betaines, 7-methylguanosine (7MeGuo) (I) and 7-methyl-2'-deoxyguanosine (7MedGuo) (II), as well as 1,7-dimethylguanosinium iodide (1,7diMeGuoI). In solvolyzing to a purine and ribose or deoxyribose, all show specific hydronium ion catalysis over acidity regions where mono-and dicationic for ms of substrate are present. Rate profiles for Guo, dGuo, and dAdo are linear even when pH ≃ pKa. 7MeGuo and 1,7diMeGuoI undergo pH-independent hydrolysis in weakly acidic soln. 7MedGuo shows two regions linearly dependent on acidity and a pH-independent region. Kinetic and equil. pKa values for 7MedGuo are identical. Guo, 7MeGuo, and 1,7diMeGuoI hydrolyze at essentially identical rates at low pH. While dGuo is 520 times more reactive than Guo, dAdo and dGuo have similar reactivity. These nucleosides hydrolyze by a mechanism involving preequil. protonation of the purine followed by rate-limiting purine-glycosyl bond cleavage.(c) Garrett, E. R.; Mehta, P. Solvolysis of adenine nucleosides. I. Effects of sugars and adenine substituents on acid solvolyses. J. Am. Chem. Soc. 1972, 94, 8532– 8541, DOI: 10.1021/ja00779a040[ACS Full Text.], [CAS], Google Scholar199chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE3sXjtVWhtg%253D%253D&md5=43b80f53b4755f74b1b3cdb982e90c14Solvolysis of adenine nucleosides. I. Effects of sugars and adenine substituents on acid solvolysesGarrett, Edward R.; Mehta, P. J.Journal of the American Chemical Society (1972), 94 (24), 8532-41CODEN: JACSAT; ISSN:0002-7863.The acidic solvolyses of 2',3'-dideoxyadenosine > 2'-deoxyadenosine > 9-β-D-psicofuranosyladenine » 3'-deoxyadenosine > 8-bromoadenosine > 9-β-D-arabinofuranosyladenine ∼ 2-chloroadenosine ∼ N6-methyladenosine ⪆ adenosine ∼ 2-methyladenosine > 1-methyladenosine ∼ N6,N6-dimethyladenosine ⪆ 9-β-D-xylofuranosyladenine > 8-methoxyadenosine ∼ 2'-C-methyladenosine gave the resp. sugar and stable adenine moiety except in the case of where the resultant 1-methyladenine was more slowly transformed into 5-aminoimidazole-4-N'-methylcarboxamidine. The ranking of relative activities are given above for 80° in 0.10M HCl. Only specific acid catalyzed solvolyses of the protonated and non-protonated species were obsd. and there was no max. in solvolysis rate in the low pH region, supporting the argument against a Schiff base intermediate subsequent to ethereal oxygen attack. The probability of an A-1 mechanism for solvolyses of diprotonated adenine nucleosides with protons on the nitrogens in the 1 and 7 positions was favored by the fact that the entropies of activation, ΔS⧺, were close to zero. Although the inductive effect of the 2'-OH inhibited acid solvolysis, a less significant increase in reactivity was introduced by the substitution of a hydrogen for the 3'-OH. The effects of substituents on the pyrimidine ring lead to only minor effects in reactivity whereas substitution of Br or MeO on C-8 of the imidazole portion has a more pronounced effect. The 1-methyladenosine cation solvolyzes in acid at about the same rate as the adenosine cation strongly suggesting that it is the 1-protonated form of the latter that reacts with a second proton to result in a solvolyzing dication.(d) York, J. L. Effect of the structure of the glycon on the acid-catalyzed hydrolysis of adenine nucleosides. J. Org. Chem. 1981, 46, 2171– 2173, DOI: 10.1021/jo00323a040[ACS Full Text.], [CAS], Google Scholar199dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL3MXhvFalsLc%253D&md5=891eee07185cd588fe3aac2849f1a0d0Effect of the structure of the glycon on the acid-catalyzed hydrolysis of adenine nucleosidesYork, J. LyndalJournal of Organic Chemistry (1981), 46 (10), 2171-3CODEN: JOCEAH; ISSN:0022-3263.The second order rate consts. were detd. for the acid-catalyzed hydrolysis at 40° of 10 adenine furanosides and 1 pyranoside. Lability of the glycosyl-adenine bond was correlated with the configuration of the adenine with respect to the 2' and/or 3' hydroxyls, the sterically unfavorable all cis arrangement being most labile. Removal of the 2', 3', or 5' hydroxyls increases the rate of hydrolysis. A reverse D solvent isotope effect was obsd. for the anomeric 2'-deoxyribonucleosides. The entropy of activation was + 1.16 eu and + 4.39 eu for the furanoside and pyranoside of β and α-2'-deoxyribosyladenine, resp. The data are consistent with the A-1 mechanism of hydrolysis.(e) Gates, K. S. An overview of chemical processes that damage cellular DNA: spontaneous hydrolysis, alkylation, and reactions with radicals. Chem. Res. Toxicol. 2009, 22, 1747– 1760, DOI: 10.1021/tx900242k[ACS Full Text], [CAS], Google Scholar199ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtFemu7bI&md5=0fb1b99341b7f09b6b5f70e5f9d0ffcbAn overview of chemical processes that damage cellular DNA: Spontaneous hydrolysis, alkylation, and reactions with radicalsGates, Kent S.Chemical Research in Toxicology (2009), 22 (11), 1747-1760CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)A review. The sequence of heterocyclic bases on the interior of the DNA double helix constitutes the genetic code that drives the operation of all living organisms. With this said, it is not surprising that chem. modification of cellular DNA can have profound biol. consequences. Therefore, the org. chem. of DNA damage is fundamentally important to diverse fields including medicinal chem., toxicol., and biotechnol. This review is designed to provide a brief overview of the common types of chem. reactions that lead to DNA damage under physiol. conditions.
- 200Pogocki, D.; Schöneich, C. Chemical stability of nucleic acid-derived drugs. J. Pharm. Sci. 2000, 89, 443– 456, DOI: 10.1002/(SICI)1520-6017(200004)89:4<443::AID-JPS2>3.3.CO;2-N[Crossref], [PubMed], [CAS], Google Scholar200https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXis12ktb0%253D&md5=de5ac9d7a5951d7111e2e3b30307efb0Chemical stability of nucleic acid-derived drugsPogocki, Dariusz; Schoneich, ChristianJournal of Pharmaceutical Sciences (2000), 89 (4), 443-456CODEN: JPMSAE; ISSN:0022-3549. (Wiley-Liss, Inc.)A review with 124 refs. Nucleic acid-derived drugs exhibit both chem. and phys. instability. This mini-review focuses on the prevalent hydrolytic and oxidative pathways of chem. degrdn. as they are affected by various endogenous (primary structure, chem. modifications in bases, sugars and phosphate residues) and exogenous (pH, buffer concn., metal cation presence, oxygen presence) factors.
- 201(a) Minami, T.; Nakagawa, H.; Nabeshima, M.; Kadota, E.; Namikawa, K.; Kawaki, H.; Okazaki, Y. Nephrotoxicity induced by adenine and its analogues: relationship between structure and renal injury. Biol. Pharm. Bull. 1994, 17, 1032– 1037, DOI: 10.1248/bpb.17.1032[Crossref], [PubMed], [CAS], Google Scholar.201ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXivFymurs%253D&md5=5d1a870355e81816ed27b5ef36926756Nephrotoxicity induced by adenine and its analogs: relationship between structure and renal injuryMinami, Takeshi; Nakagawa, Hirofumi; Nabeshima, Masayoshi; Kadota, Eizi; Namikawa, Kiyohiro; Kawaki, Hideko; Okazaki, YukoBiological & Pharmaceutical Bulletin (1994), 17 (8), 1032-7CODEN: BPBLEO; ISSN:0918-6158. (Pharmaceutical Society of Japan)Twenty-four adenine analogs were administered to mice and the relation between the structure of the analogs and the occurrence of renal injury was examd. Plasma urea nitrogen (UN) and creatinine levels were measured 24 h after oral administration of the analogs. Both levels increased in the adenine-, 8-azaadenine-, isoguanine-, or 6-dimethylaminopurine (6-DMAP)-administered group, but did not increase in the other analog groups. From light microscopy, the damages of tubuli, mainly of proximal tubuli, were obsd. in the kidneys of these 4 groups. The common property of these compds. is the strong basicity of nitrogen which binds the 6-position of the purine ring. Furthermore, UN and creatinine increased time-dependently with i.v. administration of isoguanine. When adenine was i.v. administered, UN slightly increased at 1 h, but creatinine was unchanged. No changes were obsd. in the 6-DMAP- or 8-azaadenine-administered group. The basicity of nitrogen which binds to the 6-position of the purine ring is thus considered to be related to the occurrence of renal injury with oral administration, and isoguanine has high affinity with the kidney.(b) Philips, F. S.; Thiersch, J. B.; Bendich, A.; Borgatta, M. Adenine intoxication in relation to in vivo formation and deposition of 2,8-dioxyadenine in renal tubules. J. Pharmacol. Exp. Ther. 1952, 104, 20– 30[PubMed], [CAS], Google Scholar201bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaG38XisVWktQ%253D%253D&md5=08892515005158b29a9cc750dfd20d2eAdenine intoxication in relation to in vivo formation and deposition of 2,8-dioxyadenine in renal tubulesPhilips, Frederick S.; Thiersch, John B.; Bendich, Aaron; Borgatta, MarieJournal of Pharmacology and Experimental Therapeutics (1952), 104 (), 20-30CODEN: JPETAB; ISSN:0022-3565.In mice and rats, adenine except in quite small doses is nephrotoxic as the result of its in vivo oxidation to 2,8-dioxyadenine and deposition of the latter as cryst. occlusions in the renal tubules. The manifold effects previously ascribed to adenine intoxication are probably secondary complications of uremia.
- 202(a) Frank, K. B.; Connell, E. V.; Holman, M. J.; Huryn, D. M.; Sluboski, B. C.; Tam, S. Y.; Todaro, L. J.; Weigele, M.; Richman, D. D.; Mitsuya, H.; Broder, S.; Sim, I. S. Anabolism and mechanism of action of Ro24–5098, an isomer of 2′,3′-dideoxyadenosine (ddA) with anti-HIV activity. Ann. N. Y. Acad. Sci. 1990, 616, 408– 414, DOI: 10.1111/j.1749-6632.1990.tb17860.x[Crossref], [PubMed], [CAS], Google Scholar.202ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXlt1Kjur0%253D&md5=f9cbe05f5870d422ce8b29a45091e5c1Anabolism and mechanism of action of Ro 24-5098, an isomer of 2',3'-dideoxyadenosine (ddA) with anti-HIV activityFrank, Karl B.; Connell, Edward V.; Holman, Michael J.; Huryn, Donna M.; Sluboski, Barbara C.; Tam, Steve Y.; Todaro, Louis J.; Weigele, Manfred; Richman, Douglas D.; et al.Annals of the New York Academy of Sciences (1990), 616 (AIDS: Anti-HIV Agents, Ther., Vaccines), 408-14CODEN: ANYAA9; ISSN:0077-8923.A review with 15 refs. discussing, Ro 24-5098 (IsoddA) (I) which exhibits stability at low pH that is superior to ddA. Furthermore, IsoddA is highly resistant to enzymic degrdn. and possesses moderate anti-HIV activity in vitro. In CEM cells, phosphorylation of IsoddA to the expected antiviral metabolite, the triphosphate, occurs approx. one-third to one-fourth as readily as phosphorylation of ddA. Greater chem. and biochem. stability of the isonucleoside, however, may provide greater antiviral potency in vivo. The triphosphate of IsoddA inhibits HIV reverse transcriptase selectively with respect to DNA polymerase α. Future development of this compd. will depend upon the interaction of IsoddATP with mammalian DNA polymerases β and γ as well as toxicol. studies in animals.(b) Andrade, C. H.; de Freitas, L. M.; de Oliveira, V. Twenty-six years of HIV science: an overview of anti-HIV drugs metabolism. Braz. J. Pharm. Sci. 2011, 47, 209– 230, DOI: 10.1590/S1984-82502011000200003[Crossref], [CAS], Google Scholar.202bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXht1GktbjL&md5=4b86aa5d5680318af455f3b8b3450a9cTwenty-six years of HIV science: an overview of anti-HIV drugs metabolismAndrade, Carolina Horta; Medeiros de Freitas, Lenis; de Oliveira, ValeriaBrazilian Journal of Pharmaceutical Sciences (2011), 47 (2), 209-230CODEN: BJPSC3; ISSN:1984-8250. (Universidade de Sao Paulo, Faculdade de Ciencias Farmaceuticas)A review. From the identification of HIV as the agent causing AIDS, to the development of effective antiretroviral drugs, the scientific achievements in HIV research over the past twenty-six years have been formidable. Currently, there are twenty-five anti-HIV compds. which have been formally approved for clin. use in the treatment of AIDS. These compds. fall into six categories: nucleoside reverse transcriptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), cell entry inhibitors or fusion inhibitors (FIs), co-receptor inhibitors (CRIs), and integrase inhibitors (INIs). Metab. by the host organism is one of the most important determinants of the pharmacokinetic profile of a drug. Formation of active or toxic metabolites will also have an impact on the pharmacol. and toxicol. outcomes. Therefore, it is widely recognized that metab. studies of a new chem. entity need to be addressed early in the drug discovery process. This paper describes an overview of the metab. of currently available anti-HIV drugs.(c) Martin, J. C.; Hitchcock, M. J. M.; De Clercq, E.; Prusoff, W. H. Early nucleoside reverse transcriptase inhibitors for the treatment of HIV: A brief history of stavudine (D4T) and its comparison with other dideoxynucleosides. Antiviral Res. 2010, 85, 34– 38, DOI: 10.1016/j.antiviral.2009.10.006[Crossref], [PubMed], [CAS], Google Scholar202chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXnvFCmtA%253D%253D&md5=5323ff19629456a9039a3572cd63c78fEarly nucleoside reverse transcriptase inhibitors for the treatment of HIV: A brief history of stavudine (D4T) and its comparison with other dideoxynucleosidesMartin, John C.; Hitchcock, Michael J. M.; De Clercq, Erik; Prusoff, William H.Antiviral Research (2010), 85 (1), 34-38CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)A review. The occasion of this 25th anniversary issue encouraged us to reminisce about the important history of the discovery of the dideoxynucleoside analogs for the treatment of HIV/AIDS and to chronicle our thoughts about a particular exciting and rewarding period of our scientific careers. Following the identification of the anti-HIV activity of zidovudine (AZT), we participated in the urgent quest to discover optimal treatments of HIV infection and AIDS. A no. of previously synthesized nucleoside analogs were comparatively evaluated, and stavudine (D4T) emerged as a promising candidate for development. Following clin. evaluation, D4T became a mainstay of the initial antiretroviral combination therapy, prolonging and saving numerous lives. It has only recently been supplanted by better-tolerated treatments. This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, vol. 85, issue 1, 2010.
- 203Hirt, D.; Bardin, C.; Diagbouga, S.; Nacro, B.; Hien, H.; Zoure, E.; Rouet, F.; Ouiminga, A.; Urien, S.; Foulongne, V.; Van De Perre, P.; Treuyer, J.; Msellati, P. Didanosine population pharmacokinetics in west african human immunodeficiency virus-infected children administered once-daily tablets in relation to efficacy after one year of treatment. Antimicrob. Agents Chemother. 2009, 53, 4399– 4406, DOI: 10.1128/AAC.01187-08[Crossref], [PubMed], [CAS], Google Scholar203https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXht1KkurvE&md5=0a95237e7134b29277e43d32b359cd6aDidanosine population pharmacokinetics in West African human immunodeficiency virus-infected children administered once-daily tablets in relation to efficacy after one year of treatmentHirt, Deborah; Bardin, Christophe; Diagbouga, Serge; Nacro, Boubacar; Hien, Herve; Zoure, Emmanuelle; Rouet, Francois; Ouiminga, Adama; Urien, Saik; Foulongne, Vincent; Van De Perre, Philippe; Treluyer, Jean-Marc; Msellati, PhilippeAntimicrobial Agents and Chemotherapy (2009), 53 (10), 4399-4406CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)Our objective was to study didanosine pharmacokinetics in children after the administration of tablets, the only formulation available in Burkina Faso for which data are missing, and to establish relationships between doses, plasma drug concns., and treatment effects (efficacy/toxicity). Didanosine concns. were measured for 40 children after 2 wk and for 9 children after 2 to 5 mo of treatment with a didanosine-lamivudine-efavirenz combination. A population pharmacokinetic model was developed with NONMEM. The link between the maximal concn. of the drug in plasma (Cmax), the area under the concn.-time curve (AUC), and the decrease in human immunodeficiency virus (HIV) type 1 RNA levels after 12 mo of treatment was evaluated. The threshold AUC that improved efficacy was detd. by the use of a Wilcoxon test for HIV RNA, and an optimized dosing schedule was simulated. Didanosine pharmacokinetics was best described by a one-compartment model with first-order absorption and elimination. The apparent clearance and vol. of distribution were higher for tablets, probably due to a lower bioavailability with tablets than with pediatric powder. The decrease in the viral load after 12 mo of treatment was significantly correlated with the didanosine AUC and Cmax (P ≤ 0.02) during the first weeks of treatment. An AUC of > 0.60 mg/L/h was significantly linked to a greater decrease in the viral load (a decrease of 3 log10 vs. 2.4 log10 copies/mL; P = 0.03) than that with a lower AUC. A didanosine dose of 360 mg/m2 administered as tablets should be a more appropriate dose than 240 mg/m2 to improve efficacy for these children. However, data on adverse events with this dosage are missing.
- 204(a) Kelley, J. A.; Litterst, C. L.; Roth, J. S.; Vistica, D. T.; Poplack, D. G.; Cooney, D. A.; Nadkarni, M.; Balis, F. M.; Broder, S.; Johns, D. G. The disposition and metabolism of 2′,3′-dideoxycytidine, an in vitro inhibitor of human T-lymphotrophic virus type III infectivity, in mice and monkeys. Drug Metab. Dispos. 1987, 15, 595– 601[PubMed], [CAS], Google Scholar.204ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1cXjtFaitg%253D%253D&md5=8afe4c7180c231a954dae698d99083c0The disposition and metabolism of 2',3'-dideoxycytidine, an in vitro inhibitor of human T-lymphotrophic virus type III infectivity, in mice and monkeysKelley, James A.; Litterst, Charles L.; Roth, Jeri S.; Vistica, David T.; Poplack, David G.; Cooney, David A.; Nadkarni, Mohan; Balis, Frank M.; Broder, Samuel; Johns, David G.Drug Metabolism and Disposition (1987), 15 (5), 595-601CODEN: DMDSAI; ISSN:0090-9556.The pharmacokinetics and metab. of the anti-human T-lymphotrophic virus type III/lymphadenopathy-assocd. virus agent 2',3-dideoxycytidine were examd. in BDF1 mice and rhesus monkeys, with ancillary enzyme studies carried out on tissue derived from both the latter species and also from human subjects. For the pharmacokinetic studies, 2',3'-dideoxycytidine and its catabolic product 2',3'-dideoxyuridine were sepd. and measured in plasma, urine, and cerebrospinal fluid by a reverse HPLC method. For metabolic studies, 3H-labeled drug (labeled in the 5- and 6-positions of the pyrimidine ring) was employed, utilizing an ion exchange HPLC anal. method suitable for the sepn. of the parent nucleoside from its mono-, di-, and triphosphates in cell exts. and in tissue homogenates. The drug was rapidly cleared from plasma in a biphasic manner (terminal t1/2 in BDF1 mice and rhesus monkeys of 67 min and 109 min, resp.) following an i.v. bolus dose of 325 mg/m2. This 2-compartment open model was predictive of plasma concns. during long term i.p. infusions in mice. Dideoxycytidine was predominantly excreted in the urine as unchanged parent compd., although a minor urinary metabolite (2',3'-dideoxyuridine) was detected in the monkey but not in the mouse. Oral absorption of 2',3'-dideoxycytidine was rapid, with plasma levels approaching those seen after i.v. administration within 45 min in the mouse. Entry to the central nervous system was also rapid, but the cerebrospinal fluid to plasma area under concn.-time curve ratio after i.v. administration was only 0.026-0.040 in rhesus monkeys. Relatively high tissue levels were seen in mouse kidneys, pancreas, and liver after either single bolus i.v. injection or long-term (7-day) i.p. infusion. The drug appeared in tissues mainly as the parent nucleoside, with its pharmacol. active anabolite (2',3'-dideoxycytidine 5'-triphosphate) accounting for only a small fraction (<2%) of retained drug.(b) Klecker, R. W., Jr.; Collins, J. M.; Yarchoan, R. C.; Thomas, R.; McAtee, N.; Broder, S.; Myers, C. E. Pharmacokinetics of 2′,3′-dideoxycytidine in patients with AIDS and related disorders. J. Clin. Pharmacol. 1988, 28, 837– 842, DOI: 10.1002/j.1552-4604.1988.tb03225.x[Crossref], [PubMed], [CAS], Google Scholar204bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL1M7lsF2juw%253D%253D&md5=e1c6b2b914395421cd15b9cc5ea2bc22Pharmacokinetics of 2',3'-dideoxycytidine in patients with AIDS and related disordersKlecker R W Jr; Collins J M; Yarchoan R C; Thomas R; McAtee N; Broder S; Myers C EJournal of clinical pharmacology (1988), 28 (9), 837-42 ISSN:0091-2700.The clinical pharmacokinetics of 2',3'-dideoxycytidine (DDC) were determined after oral and intravenous administration in ten patients with AIDS or AIDS-related complex. A high performance liquid chromatography (HPLC) analysis procedure using cation exchange extraction columns was used to measure DDC levels as low as 0.1 microM (21 ng/mL) in plasma and urine. The kinetics of DDC were linear over the dose range of 0.03 to 0.5 mg/kg. Total body clearance was 227 mL/min/m2 and did not change after 6 to 14 days of dosing. The volume of distribution at steady state was 0.54 L/kg. Plasma half-life was 1.2 hours, and bioavailability was 88%. Most (75%) of the parent drug was found unchanged in the urine. As a result, renal function could play a role in dose adjustment of DDC. Comparison is made between the kinetics of DDC and 3'-azido-2',3'-dideoxythymidine (AZT). Similarities are noted in half-life and bioavailability. However, differences are observed for total body clearance, cerebrospinal fluid penetration, volume of distribution, metabolism, and recovery in urine.
- 205(a) Marquez, V. E.; Tseng, C. K.; Mitsuya, H.; Aoki, C.; Kelley, J. A.; Ford, H.; Roth, J. S.; Broder, S.; Johns, D. G.; Driscoll, J. S. Acid-stable 2′-fluoro purine dideoxynucleosides as active agents against HIV. J. Med. Chem. 1990, 33, 978– 985, DOI: 10.1021/jm00165a015[ACS Full Text.], [CAS], Google Scholar205ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3cXhvFWnsbg%253D&md5=98df7896ad6c34fde7c15f8324422e19Acid-stable 2'-fluoro purine dideoxynucleosides as active agents against HIVMarquez, Victor E.; Tseng, Christopher K. H.; Mitsuya, Hiroaki; Aoki, Shizuko; Kelley, James A.; Ford, Harry, Jr.; Roth, Jeri S.; Broder, Samuel; Johns, David G.; Driscoll, John S.Journal of Medicinal Chemistry (1990), 33 (3), 978-85CODEN: JMCMAR; ISSN:0022-2623.2',3'-Dideoxypurine nucleosides have anti-HIV activity in vitro and the inosine analog is being clin. evaluated. The instability of these compds. toward acidic conditions complicates oral administration. The effect of the addn. of a F to the 2'-position was investigated by prepg. the fluorine-contg. 2'-erythro and 2'-threo isomers of 2',3'-dideoxyadenosine (ddA) and the threo isomer of 2',3'-dideoxyadenosine (ddI). All F-contg. compds. were indefinitely stable to acidic conditions which completely decompd. ddI and ddA in minutes. While the fluorine-contg. erythro isomer, (I), was inactive, the threo isomers, 2'-F-dd-ara-A (II) and 2'-F-dd-ara-I (III), were just as potent and active in protecting CD4+ ATH8 cells from the cytopathogenic effects of HIV-1 as the parent drugs. Exposure to pH 1 at 37° prior to testing destroyed the activity of ddA and ddI but left the anti-HIV properties of II and III unchanged. The fluorinated analogs also protected cells exposed to HIV-2 and inhibited gag gene product expression but not as effectively as the parent compds. The fluorine-contg. analogs appear to be somewhat more toxic in vitro to the antigen- and mitogen-driven proliferation of immunocompetent cells than their corresponding parent compds.(b) Marquez, V. E.; Tseng, C. K.-H.; Kelley, J. A.; Mitsuya, H.; Broder, S.; Roth, J. S.; Driscoll, J. S. 2′,3′-Dideoxy-2′-fluoro-ara-A. An acid-stable purine nucleoside active against human immunodeficiency virus (HIV). Biochem. Pharmacol. 1987, 36, 2719– 2722, DOI: 10.1016/0006-2952(87)90254-1[Crossref], [PubMed], [CAS], Google Scholar.205bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1cXhvF0%253D&md5=d5ecc6950761ff16fdcff2ca32c50de52',3'-Dideoxy-2'-fluoro-ara-A. An acid-stable purine nucleoside active against human immunodeficiency virus (HIV)Marquez, Victor E.; Tseng, Christopher K. H.; Kelley, James A.; Mitsuya, Hiroaki; Broder, Samuel; Roth, Jeri S.; Driscoll, John S.Biochemical Pharmacology (1987), 36 (17), 2719-22CODEN: BCPCA6; ISSN:0006-2952.Diastereoisomers of 2'-monofluorodideoxyadenosine (I) were prepd. and tested for acid stability and protective action against HIV-induced cytopathy in cell culture. Whereas the compd. with the down configuration (I, R = H; R1 = F) was less stable and less active than the parent compd. dideoxyadenosine, the compd. with the up configuration (I, R = F; R1 = H) was as active as the known drugs AZT (3'-azido-3'-deoxythymidine) in protection against HIV-induced cytopathy and also was stable to acid conditions, such as is encountered in the stomach. Thus, I (R = F; R1 = H) appears to be a promising drug in the management of HIV infections. Structure-activity relationship is discussed.(c) Russell, J. W.; Klunk, L. J. Comparative pharmacokinetics of new anti-HIV agents: 2′, 3′-dideoxyadenosine and 2′, 3′-dideoxyinosine. Biochem. Pharmacol. 1989, 38, 1385– 1388, DOI: 10.1016/0006-2952(89)90176-7[Crossref], [PubMed], [CAS], Google Scholar205chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1MXktlejtrw%253D&md5=bd48d88280bf38d1a269bca353a830c6Comparative pharmacokinetics of new anti-HIV agents: 2',3'-dideoxyadenosine and 2',3'-dideoxyinosineRussell, John W.; Klunk, Lewis J.Biochemical Pharmacology (1989), 38 (9), 1385-8CODEN: BCPCA6; ISSN:0006-2952.The conversion of 2',3'-dideoxyadenosine (ddA) to 2',3'-dideoxyinosine (ddI) was studied in mice to det. suitability of measuring plasma levels of ddI and to assess the bioavailability and pharmacokinetics of dDA. The conversion of ddA to ddI in collected blood plasma had a half-life of 45 min to 6 h depending on the extent of hemolysis because adenosine deaminase involved in the conversion is located mainly in erythrocytes. In vivo conversion was very fast; within 5 min after i.v. administration of 25 mg ddA/kg no ddA was detectable in blood. Thus, the pharmacokinetics of ddA can be evaluated by ddI levels in blood. Both agents administered orally were partially degraded in the stomach and showed an incomplete bioavailability.
- 206(a) Liu, P.; Sharon, A.; Chu, C. K. Fluorinated nucleosides: synthesis and biological implication. J. Fluorine Chem. 2008, 129, 743– 766, DOI: 10.1016/j.jfluchem.2008.06.007[Crossref], [PubMed], [CAS], Google Scholar.206ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtVyitrnL&md5=01c8d8c393e35144095e4c31e505dd89Fluorinated nucleosides: Synthesis and biological implicationLiu, Peng; Sharon, Ashoke; Chu, Chung K.Journal of Fluorine Chemistry (2008), 129 (9), 743-766CODEN: JFLCAR; ISSN:0022-1139. (Elsevier B.V.)The present review deals with the synthetic methodol., structural and biol. implication of carbohydrate-modified fluoronucleosides. A no. of important pharmaceuticals have been discovered and developed based on fluorinated analogs of biol. active nucleosides. The introduction of fluorine into a nucleoside structure at an appropriate position has modulated and/or improved the pharmacol. properties of a mol.(b) Wójtowicz-Rajchel, H. Synthesis and applications of fluorinated nucleoside analogues. J. Fluorine Chem. 2012, 143, 11– 48, DOI: 10.1016/j.jfluchem.2012.06.026[Crossref], [CAS], Google Scholar206bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsVyktrjE&md5=df4a032247b009439fcc6b2cab92116bSynthesis and applications of fluorinated nucleoside analoguesWojtowicz-Rajchel, HannaJournal of Fluorine Chemistry (2012), 143 (), 11-48CODEN: JFLCAR; ISSN:0022-1139. (Elsevier B.V.)The review presents the synthesis of fluorinated highly modified nucleoside analogs-carbanucleosides, arom. nucleosides, acyclic nucleosides and related derivs.
- 207Rozen, S.; Vints, I.; Lerner, A.; Hod, O.; Brothers, E. N.; Moncho, S. The chemistry of short-lived α-fluorocarbocations. J. Org. Chem. 2021, 86, 3882– 3889, DOI: 10.1021/acs.joc.0c02731[ACS Full Text], [CAS], Google Scholar207https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXksFWktbk%253D&md5=ebe1f9e22f2214d83014155f2c6da09aThe Chemistry of Short-Lived α-FluorocarbocationsRozen, Shlomo; Vints, Inna; Lerner, Ana; Hod, Oded; Brothers, Edward N.; Moncho, SalvadorJournal of Organic Chemistry (2021), 86 (5), 3882-3889CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)The present study of the chem. of short-lived α-fluorocarbocations reveals that even inactive Me carbons can serve as nucleophiles, attacking a cationic center. This, in turn, facilitates the synthesis of a cyclopropane ring in certain triterpene backbones. We report the synthesis of compds. similar to 2, contg. a bridgehead cyclopropane, and compds. of type 3 with an 11 membered bicyclic ring consisting of two bridgehead double bonds (anti-Bredt) within a triterpene skeleton. The synthesis involves three unconventional chem. processes: (a) a Me group serving as a nucleophile; (b) the unexpected and unprecedented synthesis of a strained system in the absence of an external neighboring trigger; and (c) the formation of an 11-membered bicyclic diene ring within a triterpenoid skeleton. An α-fluorocarbocation mechanism is proposed and supported by d. functional theory calcns.
- 208Johnson, S. A. Nucleoside analogues in the treatment of haematological malignancies. Expert Opin. Pharmacother. 2001, 2, 929– 943, DOI: 10.1517/14656566.2.6.929[Crossref], [PubMed], [CAS], Google Scholar208https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXkvVKmtbc%253D&md5=97874da0b9574126f88a62bc4edf32e9Nucleoside analogues in the treatment of haematological malignanciesJohnson, Stephen A.Expert Opinion on Pharmacotherapy (2001), 2 (6), 929-943CODEN: EOPHF7; ISSN:1465-6566. (Ashley Publications Ltd.)A review with refs. The nucleoside analogs are a group of antimetabolite cytotoxics which generally have to be metabolized to the equiv. nucleotide before incorporation into DNA. Cytarabine is a well established component of the treatment of acute leukemias and has its principal action on dividing cells. New formulations include a liposome encapsulated product for intrathecal use and oral cytarabine ocfosfate which may be suitable for long-term outpatient use. Pentostatin acts by causing accumulation of deoxynucleotides and, although active against hairy cell leukemia, is assocd. with a poor tolerance profile. Cladribine and fludarabine have substantial activity in the treatment of chronic lymphocytic leukemia (CLL) and low-grade non-Hodgkin's lymphoma (NHL). Fludarabine is the more thoroughly investigated of the two and is currently being developed in combination therapies for CLL and NHL and also in a combination with cytarabine for acute myeloid leukemia. Fludarabine's immunosuppressive activity is being exploited in the conditioning of patients for non-myeloablative stem cell transplantation. Gemcitabine is an established agent in the treatment of a no. of solid tumors but also has activity in haematol. malignancies which might be exploited by the use of extended infusion schedules. Newer agents including nelarabine, clofarabine and troxacitabine are undergoing clin. evaluation and show promising activity.
- 209Avramis, V. I.; Plunkett, W. 2-Fluoro-ATP: a toxic metabolite of 9-β-d-arabinoxyl-2-fluroadenine. Biochem. Biophys. Res. Commun. 1983, 113, 35– 43, DOI: 10.1016/0006-291X(83)90428-X[Crossref], [PubMed], [CAS], Google Scholar209https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL3sXks1ektbY%253D&md5=6c839f5fc3692e6e9fa68d246b6f723d2-Fluoro-ATP: a toxic metabolite of 9-β-D-arabinosyl-2-fluoroadenineAvramis, Vassilios I.; Plunkett, WilliamBiochemical and Biophysical Research Communications (1983), 113 (1), 35-43CODEN: BBRCA9; ISSN:0006-291X.Murine P388 cells incubated in vitro with the anticancer drug 9-β-D-arabinosyl-2-fluoroadenine (I) [21679-14-1] accumulated its 5'-triphosphate, F-araATP [74832-57-8], as the major phosphorylated metabolite. A new chromatog. distinct metabolite that accumulated to 10% of F-araATP levels was identified as 2-fluoro-ATP (II) [1492-62-2], by the following criteria: (1) the metabolite coeluted with the authentic compd. on anion-exchange high-performance liq. chromatog.; (2) dephosphorylation of the metabolite yielded a compd. that was chromatog. identical to 2-fluoroadenosine; (3) the compd. was sensitive to NaIO4 oxidn. Cellular incubation expts. indicated that 2-fluoroadenine [700-49-2], but not arabinosyl-2-fluorohypoxanthine [83480-48-2], was the likely intermediate in the formation of 2-fluoro-ATP.
- 210(a) Carson, D. A.; Wasson, D. B.; Esparza, L. M.; Carrera, C. J.; Kipps, T. J.; Cottam, H. B. Oral antilymphocyte activity and induction of apoptosis by 2-chloro-2′-arabino-fluoro-2′-deoxyadenosine. Proc. Natl. Acad. Sci. U. S. A. 1992, 89, 2970– 2974, DOI: 10.1073/pnas.89.7.2970[Crossref], [PubMed], [CAS], Google Scholar.210ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK38Xit1OrsL0%253D&md5=ba2408150a5c7b3e001d65cdb64607afOral antilymphocyte activity and induction of apoptosis by 2-chloro-2'-arabino-fluoro-2'-deoxyadenosineCarson, Dennis A.; Wasson, D. Bruce; Esparza, Lucia M.; Carrera, Carlos J.; Kipps, Thomas J.; Cottam, Howard B.Proceedings of the National Academy of Sciences of the United States of America (1992), 89 (7), 2970-4CODEN: PNASA6; ISSN:0027-8424.2-Chlorodeoxyadenosine (CdA) is active in chronic lymphocytic leukemia, hairy-cell leukemia, and low-grade lymphomas. In part, this spectrum of activity may be attributable to the selective toxicity of CdA to nondividing lymphoctytes and monocytes. However, CdA is unstable at acidic pH and is degraded by bacterial nucleoside phosphorylases. The present expts. demonstrate that the 2'-arabino-fluoro deriv. of CdA, designated CAFdA, is also directly toxic to quiescent lymphocytes and macrophages. Unlike CdA, CAFdA was stable at pH 2 and resisted degrdn. by Escherichia coli nucleoside phosphorylase. Cell killing was preceded by the formation of DNA strand breaks and could be prevented by supplementation of the medium with deoxycytidine. The initial DNA damage initiated the pattern of oligonucleosomal DNA fragmentation characteristic of apoptosis. Mutant lymphoblasts, deficient in deoxycytidine kinase, with elevated cytoplasmic 5'-nucleotidase, or with expanded deoxynucleotide pools secondary to increased ribonucleotidase, or with expanded deoxynucleotide pools secondary to increased ribonucleotide reductase activity, were cross-resistant to both CAFdA and CdA toxicity. One-week oral treatment with CAFdA (1 mg/mL in drinking water) achieved an av. plasma concn. of 0.56 μM and eliminated 90% of chronic lymphocytic leukemia cells transplanted into severe combined immunodeficiency (scid) mice. Under the same conditions, CdA was much less active. Collectively, these results suggest that CAFdA could be effective as and oral agent in indolent lymphoproliferative diseases and in autoimmune diseases where lymphocyte and monocyte depletion is desirable.(b) Lindemalm, S.; Liliemark, J.; Juliusson, J.; Larsson, R.; Albertioni, F. Cytotoxicity and pharmacokinetics of cladribine metabolite, 2-chloroadenine, in patients with leukemia. Cancer Lett. 2004, 210, 171– 177, DOI: 10.1016/j.canlet.2004.03.007[Crossref], [PubMed], [CAS], Google Scholar210bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXks1WrsLk%253D&md5=33704489f7136957ac850290648c817aCytotoxicity and pharmacokinetics of cladribine metabolite, 2-chloroadenine in patients with leukemiaLindemalm, Synnove; Liliemark, Jan; Juliusson, Gunnar; Larsson, Rolf; Albertioni, FreidounCancer Letters (Amsterdam, Netherlands) (2004), 210 (2), 171-177CODEN: CALEDQ; ISSN:0304-3835. (Elsevier)The nucleoside analog 2-chlorodeoxyadenosine (Cladribine, CdA) is used in the treatment of patients with several hematol. malignancies. After administration of CdA, the major catabolite measured in plasma and urine is 2-chloroadenine (CAde). This study was performed to det. the pharmacokinetics after oral and i.v. (iv) infusion of CdA in patients treated for chronic lymphocytic leukemia and to evaluate the toxicity of CAde to leukemia cells in vitro. CdA and CAde were also detd. in plasma from 31 patients and in urine from 16 patients with reversed-phase high-performance liq. chromatog. The toxicity of CdA and CAde was also detd. in leukemic cells from 7 patients by fluorometric microculture cytotoxicity assay. Five times more CAde was quantified after oral treatment compared with an iv infusion of CdA. After iv infusion, the half-life was the same for CdA and CAde, but after oral administration the half-life was doubled for CAde. Excreted amt. of CAde in urine constituted about 1.1% after iv infusion and 4.7% after oral CdA treatment. In vitro exposure of leukemia cells to CAde showed that it was eight times less toxic as compared to CdA. We conclude that CAde has a lower cytotoxic effect than CdA but may contribute significantly to the cytotoxicity after oral administration.
- 211(a) Chilman-Blair, K.; Mealy, N. E.; Castaner, J. Clofarabine: treatment of acute leukemia. Drugs Future 2004, 29, 112– 120, DOI: 10.1358/dof.2004.029.02.776206[Crossref], [CAS], Google Scholar.211ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXivF2kur4%253D&md5=c9e78e3324853ff8ffb3b0da3a63e075Clofarabine: treatment of acute leukemiaChilman-Blair, K.; Mealy, N. E.; Castaner, J.Drugs of the Future (2004), 29 (2), 112-120CODEN: DRFUD4; ISSN:0377-8282. (Prous Science)A review. Clofarabine (Clofarex, 2-Cl-2'-F-araA, CAFdA) is a novel anticancer agent shown to be particularly effective in acute leukemia therapy. It is a second-generation purine nucleoside analog that works through incorporation into the DNA mol. and inhibition of further DNA synthesis via a no. of different mechanisms. Clofarabine is effective in many different cancers, and has proven efficacy in phase I studies in patients with solid tumors. However, clofarabine has demonstrated the most promise within the hematol. setting. Results from a no. of phase I/II studies indicated potent anticancer activity, particularly in the treatment of acute leukemias. Clofarabine is most often administered as a short 30-min i.v. infusion over 5 days per cycle, meaning that it can be delivered in an outpatient setting rather than requiring hospitalization (as opposed to first-generation analogs). Furthermore, children with resistant or refractory leukemia have exhibited total response rates of 28-44%. Clofarabine is well tolerated in this population, the most commonly reported side effects being nausea and vomiting, reversible hepatotoxicity and myelo-suppression. Promising results from phase I and II studies have led to the initiation of phase III studies in both adults and children with acute leukemia.(b) Bonate, P.; Arthaud, L.; Cantrell, W.; Stephenson, K.; Secrist, J. A.; Weitman, S. Discovery and development of clofarabine: a nucleoside analogue for treating cancer. Nat. Rev. Drug Discovery 2006, 5, 855– 863, DOI: 10.1038/nrd2055[Crossref], [PubMed], [CAS], Google Scholar.211bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtVajsbnL&md5=6d47f6d0f97231de14b598cdd0521fd0Discovery and development of clofarabine: a nucleoside analogue for treating cancerBonate, Peter L.; Arthaud, Larry; Cantrell, William R., Jr.; Stephenson, Katherine; Secrist, John A., III; Weitman, SteveNature Reviews Drug Discovery (2006), 5 (10), 855-863CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)A review. The treatment of acute leukemias, which are the most common pediatric cancers, has improved considerably in recent decades, with complete response rates approaching ∼90% in some cases. However, there remains a major need for treatments for patients who do not achieve or maintain complete remission, for whom the prognosis is very poor. In this article, the authors describe the challenges involved in the discovery and development of clofarabine, a second-generation nucleoside analog that received accelerated approval from the US FDA at the end of 2004 for the treatment of pediatric patients 1-21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens. It is the first such drug to be approved for pediatric leukemia in more than a decade, and the first to receive approval for pediatric use before adult use.(c) Montgomery, J. A.; Shortnacy-Fowler, A. T.; Clayton, S. D.; Riordan, J. M.; Secrist, J. A. Synthesis and biologic activity of 2′-fluoro-2-halo derivatives of 9-β-d-arabinofuranosyladenine. J. Med. Chem. 1992, 35, 397– 401, DOI: 10.1021/jm00080a029[ACS Full Text.], [CAS], Google Scholar211chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK38XhsFahtL8%253D&md5=515eff4888e6751ab623da12729df34bSynthesis and biological activity of 2'-fluoro-2-halo derivatives of 9-β-D-arabinofuranosyladenineMontgomery, John A.; Shortnacy-Fowler, Anita T.; Clayton, Sarah D.; Riordan, James M.; Secrist, John A., IIIJournal of Medicinal Chemistry (1992), 35 (2), 397-401CODEN: JMCMAR; ISSN:0022-2623.The synthesis of 2-halo-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)adenines I (R = Br, Cl) by coupling the 2,6-dihalopurine with 2-deoxy-2-fluoro-D-arabinofuranosyl bromide II followed by replacement of the 6-halogen with concomitant removal of the acyl blocking groups is described. 2-Fluoroadenine deriv. I (R = F) had to be prepd. by the diazotization-fluorination of 2-aminoadenine nucleoside III (R1 = NH2, R2 = Ac). All three nucleosides provided good increases in life span of mice inoculated with P388 leukemia. The best results were obtained when the compds. were administered q3h×8 on days 1, 5, and 9 after implantation of the leukemia cells. The 2',3'-dideoxynucleoside IV (R3 = H), prepd. by deacetylation of III (R1 = F, R2 = Ac) and deoxygenation of the resultant III (R1 = F, R2 = H) followed by removal of the benzoyl group of IV (R3 = Bz), was slightly active against HIV in cell culture.(d) Xie, C.; Plunke, W. Metabolism and actions of 2-chloro-9-(2-deoxy-2-fluoro-β-d-arabinofuranosyl)adenine in human lymphoblastoid cells. Cancer Res. 1995, 55, 2847– 2852[PubMed], [CAS], Google Scholar.211dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXmsFyksL4%253D&md5=00fb1bd957c0bb69f355089dea62a081Metabolism and actions of 2-chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)adenine in human lymphoblastoid cellsXie, Chunxi; Plunkett, WilliamCancer Research (1995), 55 (13), 2847-52CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)2-Chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)adenine (Cl-F-ara-A) is a new deoxyadenosine analog that is resistant to phosphorolytic cleavage and deamination. Studies with a variety of cell lines demonstrated that Cl-F-ara-A is a potent cytotoxic agent; in cell-free systems, its triphosphate (Cl-F-ara-ATP) inhibited DNA polymerase α and ribonucleotide reductase. To further characterize its mechanism of cytotoxicity, the present study investigated the cellular metab. of Cl-F-ara-A and the actions of its nucleotide metabolites in human T-lymphoblast leukemia CCRF-CEM cells. The mono-, di-, and triphosphates of Cl-F-ara-A accumulated in cells, with the monophosphate as its major metabolite. After washing cells into drug-free medium, the elimination of each Cl-F-ara-A nucleotide was nonlinear with a prolonged terminal phase. Incubation of CCRF-CEM cells with Cl-F-ara-A resulted in a incorporation of Cl-F-ara-AMP into DNA; a much lesser amt. was assocd. with RNA, suggesting that Cl-F-ara-A is a more DNA-directed compd. The site; of tissues of the analog triphosphate and the natural substrate dATP. At low Cl-F-ara-ATP:dATP values, incorporation was mainly in phosphodiester linkages at internal sites, whereas at higher Cl-F-ara-ATP:dATP values, Cl-F-ara-AMP was principally detected at terminal sites. Clonogenicity assays showed a strong inverse correlation between cell survival and Cl-F-ara-AMP incorporation into DNA. These results suggest that the incorporation of Cl-F-ara-A monophosphate into DNA is crit. for the cytotoxicity of Cl-ara-A.(e) Faderl, S.; Garcia-Manero, G.; Estrov, Z.; Ravandi, F.; Borthakur, G.; Cortes, J. E.; O’Brien, S.; Gandhi, V.; Plunkett, W.; Byrd, A.; Kwari, M.; Kantarjian, H. M. Oral clofarabine in the treatment of patients with higher-risk myelodysplastic syndrome. J. Clin. Oncol. 2010, 28, 2755– 2760, DOI: 10.1200/JCO.2009.26.3509[Crossref], [PubMed], [CAS], Google Scholar.211ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXoslyktbg%253D&md5=eca1a4d2a7c6b86a6bd31675c68460fdOral clofarabine in the treatment of patients with higher-risk myelodysplastic syndromeFaderl, Stefan; Garcia-Manero, Guillermo; Estrov, Zeev; Ravandi, Farhad; Borthakur, Gautam; Cortes, Jorge E.; O'Brien, Susan; Gandhi, Varsha; Plunkett, William; Byrd, Anna; Kwari, Monica; Kantarjan, Hagop M.Journal of Clinical Oncology (2010), 28 (16), 2755-2760CODEN: JCONDN; ISSN:0732-183X. (American Society of Clinical Oncology)Efficacy and toxicity profile of orally administered clofarabine were evaluated in patients with higher-risk myelodysplastic syndrome (MDS). 32 Patients were treated, of whom 22 had intermediate-2 or high-risk disease (International Prognostic Scoring System). Median age was 70 years (range, 53 to 86), nine patients had secondary MDS, and 20 patients experienced prior therapy failure with hypomethylating agents. 3 Doses of clofarabine were evaluated: 40 mg/m2, 30 mg/m2, and 20 mg/m2 daily for 5 days. Courses were repeated every 4 to 8 wk. 8 Patients (25%) achieved complete remission (CR), three had (9%) hematol. improvement (HI), and three had (9%) clin. benefit (CB; overall response rate, 43%). Responses in patients who experience treatment failure with hypomethylating agents included CR in two (10%), HI in two (10%), and CB in two patients (10%). No patients died within 6 wk of induction. Renal failure occurred in four patients in the context of myelosuppresssion-assocd. infectious complications. Common adverse events were gastrointestinal and hepatic. Myelosuppression was common, but prolonged myelosuppression (> 42 days) was rare. The toxicity profile was better with lower doses of clofarabine, whereas response rates did not differ significantly. Oral clofarabine has achieved a response rate of 43% in patients with higher-risk MDS. The optimal dose and schedule and the appropriate patient population for such therapy remain to be further defined.(f) Hermann, R.; Karlsson, M. O.; Novakovic, A. M.; Terranova, N.; Fluck, M.; Munafo, A. The clinical pharmacology of cladribine tablets for the treatment of relapsing multiple sclerosis. Clin. Pharmacokinet. 2019, 58, 283– 297, DOI: 10.1007/s40262-018-0695-9[Crossref], [PubMed], [CAS], Google Scholar211fhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtlWntrjK&md5=06e46182e31de49c64ed4add6cb44c8eThe Clinical Pharmacology of Cladribine Tablets for the Treatment of Relapsing Multiple SclerosisHermann, Robert; Karlsson, Mats O.; Novakovic, Ana M.; Terranova, Nadia; Fluck, Markus; Munafo, AlainClinical Pharmacokinetics (2019), 58 (3), 283-297CODEN: CPKNDH; ISSN:0312-5963. (Springer International Publishing AG)A review. Cladribine Tablets (MAVENCLAD) are used to treat relapsing multiple sclerosis (MS). The recommended dose is 3.5 mg/kg, consisting of 2 annual courses, each comprising 2 treatment weeks 1 mo apart. We reviewed the clin. pharmacol. of Cladribine Tablets in patients with MS, including pharmacokinetic and pharmacometric data. Cladribine Tablets are rapidly absorbed, with a median time to reach max. concn. (Tmax) of 0.5 h (range 0.5-1.5 h) in fasted patients. When administered with food, absorption is delayed (median Tmax 1.5 h, range 1-3 h), and max. concn. (Cmax) is reduced by 29% (based on geometric mean). Area under the concn.-time curve (AUC) is essentially unchanged. Oral bioavailability of cladribine is approx. 40%, pharmacokinetics are linear and time-independent, and vol. of distribution is 480-490 L. Plasma protein binding is 20%, independent of cladribine plasma concn. Cladribine is rapidly distributed to lymphocytes and retained (either as parent drug or its phosphorylated metabolites), resulting in approx. 30- to 40-fold intracellular accumulation vs. extracellular concns. as early as 1 h after cladribine exposure. Cytochrome P 450-mediated biotransformation of cladribine is of minor importance. Cladribine elimination is equally dependent on renal and non-renal routes. In vitro studies indicate that cladribine efflux is minimally P-glycoprotein (P-gp)-related, and clin. relevant interactions with P-gp inhibitors are not expected. Cladribine distribution across membranes is primarily facilitated by equilibrative nucleoside transporter (ENT) 1, concentrative nucleoside transporter (CNT) 3 and breast cancer resistance protein (BCRP), and there is no evidence of any cladribine-related effect on heart rate, atrioventricular conduction or cardiac repolarisation (QTc interval prolongation). Cladribine Tablets are assocd. with targeted lymphocyte redn. and durable efficacy, with the exposure-effect relationship showing the recommended dose is appropriate in reducing relapse risk.
- 212(a) Bolwell, B. J.; Cassileth, P. A.; Gale, R. P. High dose cytarabine: a review. Leukemia 1988, 2, 253– 260[PubMed], [CAS], Google Scholar.212ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL1c3jtFOmsQ%253D%253D&md5=88ea5104cf80d212fac1032c1dc6559dHigh dose cytarabine: a reviewBolwell B J; Cassileth P A; Gale R PLeukemia (1988), 2 (5), 253-60 ISSN:0887-6924.High dose cytarabine (HDARAC) therapy is used increasingly to treat hematologic malignancies. Recent data indicate that HDARAC at doses of 2-3 g/M2 every 12 hr x 10-12 doses is of comparable or greater efficacy in remission induction as standard doses of cytarabine in acute myelogenous leukemia. HDARAC can also produce remissions in individuals resistant to conventional doses. HDARAC-containing regimens are reported to result in substantially higher long-term, disease-free survival than previous approaches to post-remission therapy, but this has not yet been confirmed in controlled trials. HDARAC is also active in acute lymphocytic leukemia. Because intravenous HDARAC achieves high levels in the spinal fluid, it is useful to treat central nervous system leukemia and may provide adequate CNS prophylaxis in acute lymphocytic leukemia. HDARAC is reported to be active in advanced non-Hodgkin lymphomas and chronic myelogenous leukemia in acute phase; optimal use in these settings is under study. HDARAC has also been combined with other drugs. Randomized trials are needed to determine whether these combinations are more effective than HDARAC alone. Apart from potent myelosuppression, the dose-limiting toxicity of HDARAC is cerebellar damage. This occurs with increased frequency in patients greater than 50 years old. HDARAC is active in hematologic malignancies and may further improve therapeutic results if combined with other drugs.(b) Capizzi, R. L.; White, J. C.; Powell, B. L.; Perrino, F. Effect of dose on the pharmacokinetic and pharmacodynamic effects of cytarabine. Semin. Hematol. 1991, 28, 54– 69[PubMed], [CAS], Google Scholar212bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXmt1amsLw%253D&md5=461fef418a4b00006d24e7aea44499dfEffect of dose on the pharmacokinetic and pharmacodynamic effects of cytarabineCapizzi, Robert L.; White, J. Courtland; Powell, Bayard L.; Perrino, FredSeminars in Hematology (1991), 28 (3, Suppl. 4), 54-69CODEN: SEHEA3; ISSN:0037-1963.A review with 100 refs. on the treatment of leukemia with cytarabine.
- 213(a) Bergmann, W.; Feeney, R. J. Contributions to the study of marine products. The nucleosides of sponges. J. Org. Chem. 1951, 16, 981– 987, DOI: 10.1021/jo01146a023[ACS Full Text.], [CAS], Google Scholar213ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaG38Xjt1OnsA%253D%253D&md5=5f079e325324ccde033e002d05d355f0Marine products. XXXII. The nucelosides of sponges. IBergmann, Werner; Feeney, Robert J.Journal of Organic Chemistry (1951), 16 (), 981-7CODEN: JOCEAH; ISSN:0022-3263.Sponges of the species Cryptotethia crypta (I) from the coast of Florida, vacuum dried at 60° (600 g.), contg. 40% ash, are ground and extd. 2 days in a Soxhlet with Me2CO, giving 9.01 g. cryst. material. It is extd. with 400 cc. boiling EtOH, leaving 1.5 g. spongothymidine (II), clusters of prisms from H2O, m. 246-7°, [α]D25 81°, 80° (17.9, 33.5 mg. in 3.09 cc. 8% NaOH), [α]D 92° (27.3 mg. in 3.09 cc. C5H5N),λmax. 269mμ. From the cooled EtOH ext. another 2.4 g. II, m. 244°, is obtained. Titrating 59.4 mg. II according to Lythgoe and Todd (C.A. 39, 912.1) results in the consumption of 49.8 mg. NaIO4 or a 1.0 molar amt. Benzoylation of 150 mg. II with BzCl and 4% NaOH gives II tribenzoate, m. 190-1°; tri-p-bromobenzoate, rod-shaped crystals, m. 251-2°. Heating 630 mg. II in 10% H2SO4 3 hrs. at 130-40° and cooling the hot filtered soln. gives thymine, m. 321° with sublimation. Concn. of the original Me3CO mother liquor gives 0.3 g. of a compd., C11H15N5O5, called spongosine (III), crystals from H2O and from EtOH, m. 192-3°, [α]D25 -42.5° (24.6 mg. in 3.09 cc. 8% NaOH), which shows 1 λmax. in 0.1 N NaOH and 2 λmax. in 0.1 N HCl. III is probably a purine analog of II. Refluxing 1 hr. 120 mg. III with 5 cc. 0.1 N H2SO4 gives what may be a methylamino.ovrddot.oxypurine, C6H7N5O (IV), m. 278°. Treating IV in H2SO4 with NaNO2 gives a deaminated compd., C6H7N4O2, needles, m. 322-5°. Extn. of 620 g. (corresponding to 280 g. organic material) air-dried I from the Bahamas with Me2CO gives 4 g. of a semi-cryst. product which is washed with C6H6 and again extd. with Me2CO, giving a product which contained little, if any, II. A sample is refluxed several hrs. with 0.1 N H2SO4, giving thymine, m. 320-1°. The final Me2CO mother liquors of the 2 I are evapd. to dryness and the residue (2-3% of I) is sapond., giving 50% unsaponifiable material contg. about 60% sterols. They are acetylated, giving acetate fractions (V) with 1.05-1.2 double bonds. V are brominated with Br in AcOH and sepd. into insol. tetrabromide (VI) and sol. dibromide (VII). From VI only a small amt. of what seems to be poriferasteryl acetate tetrabromide, m. 187°, is obtained. VII are debrominated and recrystd., giving some clionasteryl (VIII) acetate, m. 134-5°, [α]D25 -42.5° (30.8 mg. in 3.09 cc. CHCl3), which, sapond., gives the free sterol, m. 137.5-8.5°, [α]D25 -37° (33.1 mg. in 3.06 cc. CHCl3); VIII propionate m. 116-16.5°, [α]D25 -41.3° (30.7 mg., CHCl3); VIII benzoate m. 139-9.5°, [α]D25 -17° (31.4 mg., CHCl3).(b) Bergmann, W.; Burke, D. C. Contributions to the study of marine products. The nucleosides of sponges. III. Spongothymidine and spongouridine. J. Org. Chem. 1955, 20, 1501– 1507, DOI: 10.1021/jo01128a007[ACS Full Text.], [CAS], Google Scholar213bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaG28Xlt1Klug%253D%253D&md5=7fa5f57b9fd58b73b0337883e01d3600Marine products. XXXIX. The nucleosides of sponges. III. Spongothymidine and spongouridineBergmann, Werner; Burke, Derek C.Journal of Organic Chemistry (1955), 20 (), 1501-7CODEN: JOCEAH; ISSN:0022-3263.cf. C.A. 46, 5609h; 50, 7808g. Paper chromatography of certain crude fractions of the nucleosides (I) isolated from Crypotethia crypta revealed the presence of spongothymidine (II), spongosine (III), and spongouridine (IV). These I have now been sepd. I are absorbed on a Dowex-1 resin (OH- form) and eluted with a NH4OH-NH4O2CH buffer soln. (pH 9.5) which elutes III. Further elution with a buffer of pH 8.3 gives II, thymine, uracil, and IV in the order given. IV, cubic crystals, m. 226-8°, [α]D 97° (c 0.6, 8% NaOH), 126° (c 1, H2O), pK 9.3. Heating 5 mg. IV with 2 cc. 90% HCO2H 2 hrs. at 150° and paper-chromatographing the product indicate the presence of unchanged IV and some uracil. Refluxing II 3 hrs. in 5% HCl or 5 hrs. in 10% H2SO4, or heating it in a sealed tube 2 hrs. with 10% H2SO4 at 125° or with 5% HCl-MeOH 5 hrs. at 100° leaves II unchanged. Reducing 467 mg. II in 100 cc. liquid NH8 and 5 cc. EtOH with 0.4 g. Na (cf. loc. cit.) and passing the product through Dowex (H+ form) give 400 mg. of a yellow gum (V), [α]D -51°, which by paper chromatography (BuOH-EtOH-H2O and BuOH satd. with H2O) and by ionophoresis in a borate buffer is found to contain only arabinose. When treated with phenylhydrazine V gives a phenylosazone (VI), m. 154-5°, which does not depress the m.p. of the phenylosazone (VII) from ribose. The infrared absorption spectrum of VI is identical with that of VII but differs from that of xylose. Similar reduction of 5.3 mg. IV followed by paper chromatography indicates the presence of arabinose. Periodate oxidation of adenosine, guanosine, cytidine, uridine, II, and IV (20-50 mg.) in H2O with 5 cc. 0.2808N NaIO4 shows the consumption of 1 mole iodate without the formation of HCO2H. Paper ionophoresis of II gives a migration rate of 0.50 for II and 0.68 for IV. Oxidation of 23 mg. II with 1 cc. 0.26N NaIO4 after 24 hrs. gives a soln. with [α]D 16.3°; a similar oxidation of D-glucopyranosylthymine gives a soln. with [α]D 17°; oxidation of 21 mg. IV gives a soln. with [α]D 15°, and oxidation of 25 mg. uridine a soln. with [α]D 15.2°. The results indicate that II is 3-β-D-arabofuranosylthymine and IV is 3-β-D-arabofuranosyluracil.(c) Khalifa, S. A. M.; Elias, N.; Farag, M. A.; Chen, L.; Saeed, A.; Hegazy, M.-E. F.; Moustafa, M. S.; Abd El-Wahed, A.; Al-Mousawi, S. M.; Musharraf, S. G.; Chang, F.-R.; Iwasaki, A.; Suenaga, K.; Alajlani, M.; Goransson, U.; El-Seedi, H. R. Marine natural products: a source of novel anticancer drugs. Mar. Drugs 2019, 17, 491, DOI: 10.3390/md17090491[Crossref], [CAS], Google Scholar.213chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXmsVCmurs%253D&md5=d1d83b0ccc8d517511e09b38da9d42a0Marine natural products: a source of novel anticancer drugsKhalifa, Shaden A. M.; Elias, Nizar; Farag, Mohamed A.; Chen, Lei; Saeed, Aamer; Hegazy, Mohamed-Elamir F.; Moustafa, Moustafa S.; Abd El-Wahed, Aida; Al-Mousawi, Saleh M.; Musharraf, Syed G.; Chang, Fang-Rong; Iwasaki, Arihiro; Suenaga, Kiyotake; Alajlani, Muaaz; Goeransson, Ulf; El-Seedi, Hesham R.Marine Drugs (2019), 17 (9), 491CODEN: MDARE6; ISSN:1660-3397. (MDPI AG)A review. Cancer remains one of the most lethal diseases worldwide. There is an urgent need for new drugs with novel modes of action and thus considerable research has been conducted for new anticancer drugs from natural sources, esp. plants, microbes and marine organisms. Marine populations represent reservoirs of novel bioactive metabolites with diverse groups of chem. structures. This review highlights the impact of marine organisms, with particular emphasis on marine plants, algae, bacteria, actinomycetes, fungi, sponges and soft corals. Anti-cancer effects of marine natural products in in vitro and in vivo studies were first introduced; their activity in the prevention of tumor formation and the related compd.-induced apoptosis and cytotoxicities were tackled. The possible mol. mechanisms behind the biol. effects are also presented. The review highlights the diversity of marine organisms, novel chem. structures, and chem. property space. Finally, therapeutic strategies and the present use of marine-derived components, its future direction and limitations are discussed.(d) Dyshlovoy, S. A.; Honecker, F. Marine compounds and cancer: the first two decades of XXI century. Mar. Drugs 2020, 18, 20, DOI: 10.3390/md18010020
- 214(a) Sun, Y.; Sun, J.; Shi, S.; Jing, Y.; Yin, S.; Chen, Y.; Li, G.; Xu, Y.; He, Z. Synthesis, transport and pharmacokinetics of 5′-amino acid ester prodrugs of 1-β-d-arabinofuranosylcytosine. Mol. Pharmaceutics 2009, 6, 315– 325, DOI: 10.1021/mp800200a[ACS Full Text.], [CAS], Google Scholar214ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtFM%253D&md5=b0c0eb744c81107c794d9f2f7d4077afSynthesis, Transport and Pharmacokinetics of 5'-Amino Acid Ester Prodrugs of 1-β-D-ArabinofuranosylcytosineSun, Yongbing; Sun, Jin; Shi, Shiliang; Jing, Yongkui; Yin, Shiliang; Chen, Ying; Li, Gang; Xu, Youjun; He, ZhongguiMolecular Pharmaceutics (2009), 6 (1), 315-325CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)Cytarabine (1-β-D-arabinofuranosylcytosine, ara-C, 1) suffers from low oral bioavailability due to low intestinal membrane permeability and poor metabolic stability, and i.v. infusion is usually adopted as the clin. std. dosing administration. To develop an oral alternative for 1 and utilize the intestinal oligopeptide transporter 1 (PepT1), a series of 5'-amino acid ester derivs. of 1 was synthesized to clarify which modification was the most suitable to increase the oral bioavailability of 1. Their apical-to-basolateral permeability across Caco-2 cells and the antiproliferative activity with HL-60 cells were screened. 5'-Valyl prodrug 2 demonstrated the highest permeability and was selected for further study. Glycylsarcosine (gly-sar, a typical substrate of PepT1) uptake by Caco-2 cells can be inhibited by 2 in a concn.-dependent manner, and IC50 for 2 was 2.18 ± 0.12 mM. The uptake of 2 was markedly increased in the long-term leptin-treated Caco-2 cells compared with the control Caco-2 cells, and was significantly inhibited by the excess of gly-sar, but not by L-valine. A dose-proportional pharmacokinetics was obsd. in rats when 5, 15, 30 mg/kg doses of 2 (calcd. as 1) were orally administered. The oral abs. bioavailability of 1 was 60.0% and 21.8% after 2 and 1 were orally administered to rats 30 mg/kg, resp. Following oral administration of 15 mg/kg, the absorption and bioactivation of 2 were extensive and rapid, over 98% of prodrug hydrolysis occurring before appearance in the portal vein. The in vivo dispositions of 1-β-D-arabinofuranosyluracil (ara-U), a deaminated product of 1, were investigated. Oral administration of 2 resulted in an increased 1/ara-U ratio (2.76) in the blood, much higher than that (1.25) after 1 orally taken. Overall, these results demonstrated that the PepT1-mediated absorption of 2 and the increased metabolic stability resulted in a dramatic increase in the oral bioavailability of 1 in rats and further corroborated the thought that prodrug design strategy targeting intestinal PepT1 was an important and promising strategy to improve oral bioavailability of poorly absorbed drugs.(b) Hamada, A.; Kawaguchi, T.; Nakano, M. Clinical pharmacokinetics of cytarabine formulations. Clin. Pharmacokinet. 2002, 41, 705– 718, DOI: 10.2165/00003088-200241100-00002[Crossref], [PubMed], [CAS], Google Scholar214bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XntFyrurs%253D&md5=095c5a6ccb4f1ae88bac4349f16c792eClinical pharmacokinetics of cytarabine formulationsHamada, Akinobu; Kawaguchi, Takeo; Nakano, MasahiroClinical Pharmacokinetics (2002), 41 (10), 705-718CODEN: CPKNDH; ISSN:0312-5963. (Adis International Ltd.)A review. Cytarabine (cytosine arabinoside, Ara-C) is an effective chemotherapeutic agent for the treatment of acute myelogenous leukemia and lymphocytic leukemias. As cytarabine is an S-phase-specific drug, prolonged exposure of cells to cytotoxic concns. is crit. to achieve max. cytotoxic activity. However, the activity of cytarabine is decreased by its rapid deamination to the biol. inactive metabolite uracil arabinoside. This rapid deamination is the reason for the ongoing search for effective formulations and derivs. of cytarabine that cannot be deaminated and exhibit better pharmacokinetic parameters. Protection of cytarabine from fast degrdn. and elimination has been investigated by encapsulating the drug into pharmaceutically acceptable carriers. Cytarabine derivs. have shown promise in vitro and in animal models. For example, ancitabine (cyclocytidine), enocitabine and cytarabine ocfosfate have been used clin. in Japan. Cytarabine encapsulated into multivesicular liposomes has been approved in several countries for the intrathecal treatment of lymphomatous meningitis. Although many compds. have been investigated, few cytarabine derivs. are currently available for clin. use. Further research is needed to improve the efficacy of cytarabine against hematol. and solid tumors.
- 215Zuckerman, T.; Ram, R.; Akria, L.; Koren-Michowitz, M.; Hoffman, R.; Henig, I.; Lavi, N.; Ofran, Y.; Horowitz, N. A.; Nudelman, O.; Tavor, S.; Yeganeh, S.; Gengrinovitch, S.; Flaishon, L.; Tessler, S.; Ben Yakar, R.; Rowe, J. M. BST-236, a novel cytarabine prodrug for patients with acute leukemia unfit for standard induction: a phase 1/2a study. Blood Adv. 2019, 3, 3740– 3749, DOI: 10.1182/bloodadvances.2019000468[Crossref], [PubMed], [CAS], Google Scholar215https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3MfjsVOrtw%253D%253D&md5=c701f8b6e44cd12bec7040731bb92262BST-236, a novel cytarabine prodrug for patients with acute leukemia unfit for standard induction: a phase 1/2a studyZuckerman Tsila; Hoffman Ron; Henig Israel; Lavi Noa; Ofran Yishai; Horowitz Netanel A; Nudelman Olga; Rowe Jacob M; Zuckerman Tsila; Hoffman Ron; Lavi Noa; Ofran Yishai; Horowitz Netanel A; Rowe Jacob M; Ram Ron; Akria Luiza; Koren-Michowitz Maya; Tavor Sigal; Yeganeh Shay; Gengrinovitch Stela; Flaishon Liat; Tessler Shoshi; Ben Yakar Ruth; Rowe Jacob MBlood advances (2019), 3 (22), 3740-3749 ISSN:.High-dose cytarabine is the backbone of acute myeloid leukemia (AML) treatment. Nevertheless, its use in older patients is considerably limited due to increased toxicity. BST-236 (INN aspacytarabine) is a novel cytarabine prodrug designed to deliver high-dose cytarabine to target cells with reduced systemic exposure to free cytarabine. This phase 1/2a dose-escalation study was designed to evaluate BST-236 safety, pharmacokinetics, and efficacy in older or unfit-for-intensive-therapy patients with acute leukemia. Twenty-six patients, unfit for standard therapy, who were either relapsed/refractory or newly diagnosed, received BST-236 in 6 dose-escalating cohorts (range 0.3 to 6 g/m2 per day). BST-236 was administered intravenously once daily over 60 minutes for 6 consecutive days. The median age was 76.5 (26 to 90), with 84.6% of patients ≥70 years. BST-236 was safe and well tolerated. The maximal tolerated dose was 6 g/m2 per day. Overall response rate was 29.6%. A subgroup analysis of newly diagnosed patients with AML, de novo or secondary to myelodysplastic syndrome, unfit for standard induction (median age 78), demonstrated overall response of 45.5%. The median overall survival was 6.5 months and was not reached in patients achieving complete remission. The findings of this phase 1/2 study suggest that BST-236 safely delivers high and efficacious cytarabine doses to older patients who are unfit for standard induction and lays the foundation for further studies of BST-236 in AML. This trial was registered at www.clinicaltrials.gov as #NCT02544438.
- 216Wright, J. A..; Wilson, D. P..; Fox, J. J. Fluoro sugar analogues of arabinosyl- and xylosylcytosines. J. Med. Chem. 1970, 13, 269– 272, DOI: 10.1021/jm00296a024[ACS Full Text], [CAS], Google Scholar216https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE3cXhtVWjtrY%253D&md5=9b6bf2186d3ba1a1b367b3808d66d5fdNucleosides. LXIV. Fluoro sugar analogs of arabinosyl- and xylosylcytosinesWright, John Arthur; Wilson, Dan Patrick; Fox, Jack J.Journal of Medicinal Chemistry (1970), 13 (2), 269-72CODEN: JMCMAR; ISSN:0022-2623.The syntheses of 1-(3-deoxy-3-fluoro- and -2-deoxy-2-fluoro-β-D-xylofuranosyl)cytosines (I and II) and 1-(2-deoxy-2-fluoro-α-and -β-D-arabinofuranosyl)cytosines (III and IV) from their corresponding suitably protected halogenoses are described. The susceptibility of these cytosine nucleosides (I, II, III) to cytidine deaminase was studied along with the susceptibility of several corresponding fluoro sugar adenine nucleosides to adenosine deaminase. Preliminary studies showed that in L1210 mouse leukemia suspension culture, IV has a growth inhibitory effect comparable with that of Ara-C.
- 217Pankiewicz, K. W. Fluorinated nucleosides. Carbohydr. Res. 2000, 327, 87– 105, DOI: 10.1016/S0008-6215(00)00089-6[Crossref], [PubMed], [CAS], Google Scholar217https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXlsVGrtbk%253D&md5=f0bae4f77a55fa0722e7ee2630f751c0Fluorinated nucleosidesPankiewicz, Krzysztof W.Carbohydrate Research (2000), 327 (1-2), 87-105CODEN: CRBRAT; ISSN:0008-6215. (Elsevier Science Ltd.)A review with 97 refs. covering the synthesis and biol. activity of deoxyfluoro nucleosides.
- 218(a) Hertel, L. W.; Kroin, J. S.; Misner, J. W.; Tustin, J. M. Synthesis of 2-deoxy-2,2-difluoro-d-ribose and 2-deoxy-2,2′-difluoro-d-ribofuranosyl nucleosides. J. Org. Chem. 1988, 53, 2406– 2409, DOI: 10.1021/jo00246a002[ACS Full Text.], [CAS], Google Scholar218ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1cXit1ajsbY%253D&md5=887cab7ff0e05a35d11150ec7c1bfea5Synthesis of 2-deoxy-2,2-difluoro-D-ribose and 2-deoxy-2,2'-difluoro-D-ribofuranosyl nucleosidesHertel, L. W.; Kroin, J. S.; Misner, J. W.; Tustin, J. M.Journal of Organic Chemistry (1988), 53 (11), 2406-9CODEN: JOCEAH; ISSN:0022-3263.A program to synthesize fluorinated D-ribose and fluorinated nucleosides was initiated with hopes of finding compds. of potential value as anticancer and/or antiviral agents. The approach is illustrated by a simple and stereocontrolled synthesis of 2-deoxy-2,2-difluoro-D-ribose (I). This was followed with the synthesis of a series of 1-(2-deoxy-2,2-difluororibofuranosyl)pyrimidine nucleosides. (R)-2,3-O-Isopropylideneglyceraldehyde was coupled with Et bromodifluoroacetate by using Reformatskii conditions to yield the carbon skeleton for the desired carbohydrate. Hydrolytic removal of the blocking groups with concomitant closure gave the γ-lactone II. Redn. to the γ-lactol ultimately yielded I. Functionalization of the difluoro carbohydrate with a leaving group at an anomeric position followed by displacement of the group with various pyrimidine bases yielded 1-(2-deoxy-2,2-difluororibofuranosyl)pyrimidine nucleosides.(b) Hertel, L. W.; Kroin, J. S.; Grossman, C. S.; Grindey, G. B.; Dorr, A. F.; Storiolo, A. M. V.; Plunkett, W.; Gandhi, V.; Huang, P. Synthesis and biological activity of 2′,2′-difluorodeoxycytidine (gemcitabine). ACS Symp. Ser. 1996, 639 (Biomedical Frontiers of Fluorine Chemistry), 265– 278, DOI: 10.1021/bk-1996-0639.ch019[ACS Full Text], [CAS], Google Scholar218bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28Xlsleisrc%253D&md5=d3ec17bff51d1e1bb82c3c68c31c9e46Synthesis and biological activity of 2',2'-difluorodeoxycytidine (gemcitabine)Hertel, L. W.; Kroin, J. S.; Grossman, C. S.; Grindey, Gerald B.; Dorr, A. F.; Storiolo, A. M. V.; Plunkett, W.; Gandhi, V.; Huang, P.ACS Symposium Series (1996), 639 (Biomedical Frontiers of Fluorine Chemistry), 265-278CODEN: ACSMC8; ISSN:0097-6156. (American Chemical Society)GEMZAR (gemcitabine-HCl) is a difluorinated analog of deoxy cytidine. It was initially synthesized as a novel anti-viral compd. with broad spectrum in vitro activity against both RNA and DNA viruses. However, the compd. proved to have a narrow therapeutic index when it was administered daily during the in vivo evaluation of antiviral activity. Using a staggered schedule of administration, GEMZAR was found to be a potent antitumor agent in murine and human xenograft solid tumor models. Studies showed that gemcitabine diphosphate was a ribonucleotide reductase inhibitor, whereas the triphosphate is a potent and unique terminator of DNA synthesis. In phase I studies a variety of dose schedules were investigated. Based on phase I studies including pharmacokinetic data, phase II studies were initiated. Activity was obsd. in a variety of solid tumors. The results were specially encouraging for non-small cell lung and pancreatic cancer. GEMZAR is currently undergoing registration review of the Phase III clin. trials for treatment of non-small cell lung and pancreatic cancer. A symposium report.
- 219(a) Bender, D. M.; Bao, J.; Dantzig, A. H.; Diseroad, W. D.; Law, K. L.; Magnus, N. A.; Peterson, J. A.; Perkins, E. J.; Pu, Y.; Reutzel-Edens, S. M.; Remick, D. M.; Starling, J. J.; Stephenson, G. A.; Vaid, R. K.; Zhang, D.; McCarthy, J. R. Synthesis, crystallization, and biological evaluation of an orally active prodrug of gemcitabine. J. Med. Chem. 2009, 52, 6958– 6961, DOI: 10.1021/jm901181h[ACS Full Text.], [CAS], Google Scholar219ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtlWmu7vJ&md5=447a5e55755846def3cf1eaae05a85b6Synthesis, Crystallization, and Biological Evaluation of an Orally Active Prodrug of GemcitabineBender, David M.; Bao, Jingqi; Dantzig, Anne H.; Diseroad, William D.; Law, Kevin L.; Magnus, Nicholas A.; Peterson, Jeffrey A.; Perkins, Everett J.; Pu, Yangwei J.; Reutzel-Edens, Susan M.; Remick, David M.; Starling, James J.; Stephenson, Gregory A.; Vaid, Radhe K.; Zhang, Deyi; McCarthy, James R.Journal of Medicinal Chemistry (2009), 52 (22), 6958-6961CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The design, synthesis, and biol. characterization of an orally active prodrug I of gemcitabine are described. Addnl., the identification of a novel co-crystal solid form of the compd. is presented. Valproate amide I is orally bio-available and releases gemcitabine into the systemic circulation after passing through the intestinal mucosa. The compd. has entered clin. trials and is being evaluated as a potential new anticancer agent.(b) Pratt, S. E.; Durland-Busbice, S.; Shepard, R. L.; Heinz-Taheny, K.; Iversen, P. W.; Dantzig, A. H. Human carboxylesterase-2 hydrolyzes the prodrug of gemcitabine (LY2334737) and confers prodrug sensitivity to cancer cells. Clin. Cancer Res. 2013, 19, 1159– 1168, DOI: 10.1158/1078-0432.CCR-12-1184[Crossref], [PubMed], [CAS], Google Scholar219bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjsFekt7k%253D&md5=37b16874ce4de70dea8a5e57f8aa8a0bHuman Carboxylesterase-2 Hydrolyzes the Prodrug of Gemcitabine (LY2334737) and Confers Prodrug Sensitivity to Cancer CellsPratt, Susan E.; Durland-Busbice, Sara; Shepard, Robert L.; Heinz-Taheny, Kathleen; Iversen, Philip W.; Dantzig, Anne H.Clinical Cancer Research (2013), 19 (5), 1159-1168CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)Purpose: The oral prodrug of gemcitabine LY2334737 is cleaved systemically to gemcitabine; the mechanism responsible for hydrolysis is unknown. LY2334737 cytotoxicity was tested in the NCI-60 panel; mining of microarray expression data identified carboxylesterase (CES) as a top hydrolase candidate. Studies examd. whether CES is responsible for hydrolysis and whether cellular CES expression confers prodrug sensitivity. Exptl. Design: Human recombinant CES isoenzymes were assayed for LY2334737 hydrolysis. Stable CES-overexpressing HCT-116 transfectants and a SK-OV-3 knockdown were prepd. Cell lines were tested for drug sensitivity and CES expression by quant. real time-PCR (qRT-PCR), Western blotting, and immunohistochem. staining. Bystander cytotoxicity studies were conducted with GFP-tagged PC-3 cells as the reporter cell line. Therapeutic response of the HCT-116 transfectants was evaluated in xenografts. Results: Of 3 human CES isoenzymes tested, only CES2 hydrolyzed LY2334737. Five cell lines that express CES2 responded to LY2334737 treatment. LY2334737 was less cytotoxic to a SK-OV-3 CES2 knockdown than parental cells. The drug response of CES2-transfected HCT-116 cells correlated with CES2 expression level. Bystander studies showed statistically greater PC-3-GFP growth inhibition by LY2334737 when cells were cocultured with CES2 and not mock transfectants. Oral treatment of xenograft models with 3.2 mg/kg LY2334737 once a day for 21 days showed greater tumor growth inhibition of CES2 transfectant than the mock transfectant (P ≤ 0.001). Conclusions: CES2 is responsible for the slow hydrolysis of LY2334737. Because intact prodrug circulates at high plasma levels after oral LY2334737 administration, improved response rates may be obsd. by tailoring LY2334737 treatment to patients with CES2 tumor expression. Clin Cancer Res; 19(5); 1159-68. ©2012 AACR.
- 220(a) Sofia, M. J.; Bao, D.; Chang, W.; Du, J.; Nagarathnam, D.; Rachakonda, S.; Reddy, P. G.; Ross, B. S.; Wang, P.; Zhang, H.; Bansal, S.; Espiritu, C.; Keilman, M.; Lam, H. M.; Steuer, M.; Niu, C.; Otto, M. J.; Furman, P. A. Discovery of a β-d-2′-Deoxy-2′-α-fluoro-2′-β-C-methyluridine nucleotide prodrug (PSI-7977) for the treatment of hepatitis C virus. J. Med. Chem. 2010, 53, 7202– 7218, DOI: 10.1021/jm100863x[ACS Full Text.], [CAS], Google Scholar220ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtFKmtb%252FO&md5=33d371e557e9d70562a326f97798f45cDiscovery of a β-D-2'-Deoxy-2'-α-fluoro-2'-β-C-methyluridine Nucleotide Prodrug (PSI-7977) for the Treatment of Hepatitis C VirusSofia, Michael J.; Bao, Donghui; Chang, Wonsuk; Du, Jinfa; Nagarathnam, Dhanapalan; Rachakonda, Suguna; Reddy, P. Ganapati; Ross, Bruce S.; Wang, Peiyuan; Zhang, Hai-Ren; Bansal, Shalini; Espiritu, Christine; Keilman, Meg; Lam, Angela M.; Steuer, Holly M. Micolochick; Niu, Congrong; Otto, Michael J.; Furman, Phillip A.Journal of Medicinal Chemistry (2010), 53 (19), 7202-7218CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Hepatitis C virus (HCV) is a global health problem requiring novel approaches for effective treatment of this disease. The HCV NS5B polymerase has been demonstrated to be a viable target for the development of HCV therapies. β-D-2'-Deoxy-2'-α-fluoro-2'-β-C-Me nucleosides are selective inhibitors of the HCV NS5B polymerase and have demonstrated potent activity in the clinic. Phosphoramidate prodrugs of the 5'-phosphate deriv. of the β-D-2'-deoxy-2'-α-fluoro-2'-β-C-methyluridine nucleoside were prepd. and showed significant potency in the HCV subgenomic replicon assay (<1 μM) and produced high levels of triphosphate 6 in primary hepatocytes and in the livers of rats, dogs, and monkeys when administered in vivo. The single diastereomer 51 of diastereomeric mixt. 14 was crystd., and an X-ray structure was detd. establishing the phosphoramidate stereochem. as Sp, thus correlating for the first time the stereochem. of a phosphoramidate prodrug with biol. activity. 51 (PSI-7977) was selected as a clin. development candidate.(b) Murakami, E.; Tolstykh, T.; Bao, H.; Niu, C.; Steuer, H. M. M.; Bao, D.; Chang, W.; Espiritu, C.; Bansal, S.; Lam, A. M.; Otto, M. J.; Sofia, M. J.; Furman, P. A. Mechanism of activation of PSI-7851 and its diastereoisomer PSI-7977. J. Biol. Chem. 2010, 285, 34337– 34347, DOI: 10.1074/jbc.M110.161802[Crossref], [PubMed], [CAS], Google Scholar220bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtlGktb7O&md5=28287a5f7547ab85158f594cd5fb1cd0Mechanism of Activation of PSI-7851 and Its Diastereoisomer PSI-7977Murakami, Eisuke; Tolstykh, Tatiana; Bao, Haiying; Niu, Congrong; Steuer, Holly M. Micolochick; Bao, Donghui; Chang, Wonsuk; Espiritu, Christine; Bansal, Shalini; Lam, Angela M.; Otto, Michael J.; Sofia, Michael J.; Furman, Phillip A.Journal of Biological Chemistry (2010), 285 (45), 34337-34347CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)A phosphoramidate prodrug of 2'-deoxy-2'-α-fluoro-β-C-methyluridine-5'-monophosphate, PSI-7851, demonstrates potent anti-hepatitis C virus (HCV) activity both in vitro and in vivo. PSI-7851 is a mixt. of two diastereoisomers, PSI-7976 and PSI-7977, with PSI-7977 being the more active inhibitor of HCV RNA replication in the HCV replicon assay. To inhibit the HCV NS5B RNA-dependent RNA polymerase, PSI-7851 must be metabolized to the active triphosphate form. The first step, hydrolysis of the carboxyl ester by human cathepsin A (CatA) and/or carboxylesterase 1 (CES1), is a stereospecific reaction. Western blot anal. showed that CatA and CES1 are both expressed in primary human hepatocytes. However, expression of CES1 is undetectable in clone A replicon cells. Studies with inhibitors of CatA and/or CES1 indicated that CatA is primarily responsible for hydrolysis of the carboxyl ester in clone A cells, although in primary human hepatocytes, both CatA and CES1 contribute to the hydrolysis. Hydrolysis of the ester is followed by a putative nucleophilic attack on the phosphorus by the carboxyl group resulting in the spontaneous elimination of phenol and the prodn. of an alaninyl phosphate metabolite, PSI-352707, which is common to both isomers. The removal of the amino acid moiety of PSI-352707 is catalyzed by histidine triad nucleotide-binding protein 1 (Hint1) to give the 5'-monophosphate form, PSI-7411. SiRNA-mediated Hint1 knockdown studies further indicate that Hint1 is, at least in part, responsible for converting PSI-352707 to PSI-7411. PSI-7411 is then consecutively phosphorylated to the diphosphate, PSI-7410, and to the active triphosphate metabolite, PSI-7409, by UMP-CMP kinase and nucleoside diphosphate kinase, resp.
- 221(a) Kawaguchi, T.; Fukushima, S.; Ohmura, M.; Mishima, M.; Nakano, M. Enzymatic and chemical stability of 2′,3′-dideoxy-2′,3′-didehydropyrimidine nucleosides: potential anti-acquired immunodeficiency syndrome agents. Chem. Pharm. Bull. 1989, 37, 1944– 1945, DOI: 10.1248/cpb.37.1944[Crossref], [PubMed], [CAS], Google Scholar.221ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1MXls1Sjurk%253D&md5=48e7967314da09dea63cccda454277daEnzymic and chemical stability of 2',3'-dideoxy-2',3'-didehydropyrimidine nucleosides: potential anti-acquired immunodeficiency syndrome agentsKawaguchi, Takeo; Fukushima, Shoji; Ohmura, Masayo; Mishima, Motohiro; Nakano, MasahiroChemical & Pharmaceutical Bulletin (1989), 37 (7), 1944-5CODEN: CPBTAL; ISSN:0009-2363.The enzymic and chem. stability of three 2',3'-dideoxy-2',3'-didehydropyrimidine nucleosides was studied. Chem. degrdn. of the analogs was measured in the pH range of 1.0-9.0. 2',3'-Dideoxy-2',3'-didehydrocytidine (DDCN) degraded rapidly under acidic conditions, but the chem. stability was greater under basic conditions. The chem. degrdn. of 2',3'-dideoxy-2',3'-didehydrouridine (DDUN) and 2',3'-dideoxy-2',3'-didehydrothymidine (DDTN) was not pH dependent and was faster than that of cytarabine. Enzymic degrdn. of DDCN, DDUN, and DDTN was not obsd. in human plasma, though cytarabine was degraded enzymically under the same conditions. DDCN was also not degraded in the presence of mouse kidney cytidine deaminase.(b) Shi, J.; Ray, A. S.; Mathew, J. S.; Anderson, K. S.; Chu, C. K.; Schinazi, R. F. 2,3-Didehydro-2,3-dideoxynucleosides are degraded to furfuryl alcohol under acidic conditions. Bioorg. Med. Chem. Lett. 2004, 14, 2159– 2162, DOI: 10.1016/j.bmcl.2004.02.031[Crossref], [PubMed], [CAS], Google Scholar221bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXjtVehurw%253D&md5=b77e08f102f1bcf8d9c0a7bf22591fac2',3'-Didehydro-2',3'-dideoxynucleosides are degraded to furfuryl alcohol under acidic conditionsShi, Junxing; Ray, Adrian S.; Mathew, Judy S.; Anderson, Karen S.; Chu, Chung K.; Schinazi, Raymond F.Bioorganic & Medicinal Chemistry Letters (2004), 14 (9), 2159-2162CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science B.V.)2',3'-Didehydro-2',3'-dideoxynucleosides are clin. relevant antiviral agents. These nucleosides could be degraded under acidic conditions. Acidic stability studies showed the D4N had the following increasing stability order: D4G < cyclo-D4G ≤ RVT < D4T with half-lives ranging from less than 2 min to 35 days. A concerted A-1 mechanism has been proposed for the acidic cleavage of D4-nucleosides. The cleavage products were characterized as furfuryl alc. and the corresponding nucleobase. Furfuryl alc. is an agent found in many everyday food products. The biol. results demonstrated that furfuryl alc. had neither anti-HIV activity nor cytotoxicity in vitro, suggesting the acid instability of D4-nucleosides is unlikely to have an impact on the toxicity of these nucleoside analogs in humans.
- 222Ray, A. S.; Hernandez-Santiago, B. I.; Mathew, J. S.; Murakami, E.; Bozeman, C.; Xie, M.-Y.; Dutschman, G. E.; Gullen, E.; Yang, Z.; Hurwitz, S.; Cheng, Y.-C.; Chu, C. K.; McClure, H.; Schinazi, R. F.; Anderson, K. S. Mechanism of anti-human immunodeficiency virus activity of β-d-6-cyclopropylamino-2′,3′-didehydro-2′,3′-dideoxyguanosine. Antimicrob. Agents Chemother. 2005, 49, 1994– 2001, DOI: 10.1128/AAC.49.5.1994-2001.2005[Crossref], [PubMed], [CAS], Google Scholar222https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXktFSntbs%253D&md5=2b56f435ca07d9ed9562d8382b01bf98Mechanism of anti-human immunodeficiency virus activity of β-D-6-cyclopropylamino-2',3'-didehydro-2',3'-dideoxyguanosineRay, Adrian S.; Hernandez-Santiago, Brenda I.; Mathew, Judy S.; Murakami, Eisuke; Bozeman, Carey; Xie, Meng-Yu; Dutschman, Ginger E.; Gullen, Elizabeth; Yang, Zhenjun; Hurwitz, Selwyn; Cheng, Yung-Chi; Chu, Chung K.; McClure, Harold; Schinazi, Raymond F.; Anderson, Karen S.Antimicrobial Agents and Chemotherapy (2005), 49 (5), 1994-2001CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)To better understand the importance of the oxygen in the ribose ring of planar unsatd. nucleoside analogs that target human immunodeficiency virus (HIV), a 6-cyclopropyl-substituted prodrug of 2',3'-didehydro-2',3'-dideoxyguanosine (cyclo-d4G) was synthesized, and its cellular metab., antiviral activity, and pharmacokinetic behavior were studied. Cyclo-d4G had selective anti-HIV activity in primary blood mononuclear cells (PBMCs), effectively inhibiting the LAI strain of HIV-1 by 50% at 1.1±0.1 μM while showing 50% inhibition of cell viability at 84.5 μM. The antiviral activity in PBMCs was not markedly affected by mutations of methionine to valine at position 184 or by thymidine-assocd. mutations in the viral reverse transcriptase. Mutations of leucine 74 to valine and of lysine 65 to arginine had mild to moderate resistance (as high as fivefold). Studies to delineate the mechanism of cellular metab. and activation of cyclo-d4G showed reduced potency in inhibiting viral replication in the presence of the adenosine/adenylate deaminase inhibitor 2'-deoxycoformycin, implying that the antiviral activity is due to its metab. to the 2'-dGTP analog d4GTP. Intracellular formation of sugar catabolites illustrates the chem. and potentially enzymic instability of the glycosidic linkage in d4G. Further studies suggest that cyclo-d4G has a novel intracellular phosphorylation pathway. Cyclo-d4G had a lower potential to cause mitochondrial toxicity than 2',3'-dideoxycytidine and 2',3'-didehydro-3'-deoxythymidine in neuronal cells. Also, cyclo-d4G had advantageous synergism with many currently used anti-HIV drugs. Poor oral bioavailability obsd. in rhesus monkeys may be due to the labile glycosidic bond, and special formulation may be necessary for oral delivery.
- 223(a) Rana, K. Z.; Dudley, M. N. Clinical pharmacokinetics of stavudine. Clin. Pharmacokinet. 1997, 33, 276– 284, DOI: 10.2165/00003088-199733040-00003[Crossref], [PubMed], [CAS], Google Scholar.223ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXntVGgtrY%253D&md5=629122c446989a5f7a4147f48ee85905Clinical pharmacokinetics of stavudineRana, Khurram Z.; Dudley, Michael N.Clinical Pharmacokinetics (1997), 33 (4), 276-284CODEN: CPKNDH; ISSN:0312-5963. (Adis)A review with 32 refs. Stavudine (d4T) is a pyrimidine nucleoside analog used in the treatment of human immunodeficiency virus (HIV) infection. It inhibits viral reverse transcriptase as do zidovudine (AZT), didanosine (ddI), zalcitabine (ddC) and lamivudine (3TC), which comprise the family of nucleoside HIV-reverse transcriptase inhibitors. Stavudine is currently approved by the US Food and Drug Administration for the treatment of patients who have become intolerant to or have failed to respond to zidovudine, didanosine or zalcitabine therapy. Oral administration of stavudine results in maximal concns. within 2 h and increases linearly as doses increase. The abs. oral bioavailability is high, approaching 100%. There is evidence to suggest that stavudine does not accumulate in the plasma. It distributes into total body water and appears to enter cells by non-facilitated diffusion. Penetration into the cerebrospinal fluid occurs, as does the transfer of the drug across human placental tissue. Stavudine is cleared quickly by both renal and nonrenal processes. The pharmacokinetic properties of stavudine in children are similar to those of adults. The pharmacokinetic parameters of stavudine were not affected by simultaneous administration of didanosine. It appears that stavudine at doses <2 mg/kg/day is most efficient at increasing CD4+ cell nos. While stavudine is reported to be less cytotoxic than zidovudine, the principal toxicity in humans is peripheral neuropathy and appears to be related to daily, but not cumulative, doses.(b) Becher, F.; Landman, R.; Mboup, S.; Kane, C. N.; Canestri, A.; Liegeois, F.; Vray, M.; Prevot, M. H.; Leleu, G.; Benech, H. Monitoring of didanosine and stavudine intracellular trisphosphorylated anabolite concentrations in HIV-infected patients. AIDS 2004, 18, 181– 187, DOI: 10.1097/00002030-200401230-00006[Crossref], [PubMed], [CAS], Google Scholar223bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXislars7c%253D&md5=b4dabe663adbd1cd65bfbe6c793525f5Monitoring of didanosine and stavudine intracellular trisphosphorylated anabolite concentrations in HIV-infected patientsBecher, Francois; Landman, Roland; Mboup, S.; Kane, C. Ndeye Toure; Canestri, Ana; Liegeois, Florent; Vray, Murielle; Prevot, Marie-Helene; Leleu, Ghislaine; Benech, HenriAIDS (London, United Kingdom) (2004), 18 (2), 181-187CODEN: AIDSET; ISSN:0269-9370. (Lippincott Williams & Wilkins)The purpose of this study was to det. the concns. of intracellular active anabolites of stavudine (d4T) and didanosine (DDI) and their interpatient variability in HIV-infected patients and to explore relationships between plasma and intracellular forms. This pilot study included 28 anti retroviral-naive HIV-infected patients who received d4T (40/30 mg twice daily), ddl (400/250 mg daily) and efavirenz (600 mg daily). After 6 mo of therapy, 7 mL of blood was collected between 0.5 and 16.2 h and 2.5 and 28.5 h after the last dose of d4T and ddl, resp. Plasma samples were obtained for the detn. of d4T and ddl concns. Peripheral blood mononuclear cells were prepd. for measuring intracellular d4T and ddl triphosphates (d4T-TP and ddA-TP, resp.). D4T-TP and ddA-TP concns. were above the limit of quantification in 25 of 26 compliant patients: median d4T-TP was 31 fmol/106 cells (range, 0-99) and median ddA-TP was 8 fmol/106 cells (range, 0-23). The half-life of d4T-TP was calcd. as 7 h. Interpatient variability in d4T-TP and ddA-TP concns. was 48% and 58%, resp. A significant relationship was obsd. between plasma d4T and intracellular d4T-TP. No relation was found between ddl and ddA-TP. A linear relation was obsd. between the intracellular concns. of d4T-TP and ddA-TP. This is the first time that data have been obtained on intracellular concns. of d4T-TP and ddA-TP, their intracellular pharmacokinetics and interpatient variability. Other similar studies with more patients are needed to enhance knowledge of the intracellular pharmacol. of the nucleoside reverse transcriptase inhibitors.
- 224(a) Schaeffer, H. J.; Beauchamp, L.; Miranda, de P.; Elion, G. B.; Bauer, D. J.; Collins, P. 9-(2-Hydroxyethoxymethyl)guanine activity against viruses of the herpes group. Nature 1978, 272, 583– 585, DOI: 10.1038/272583a0[Crossref], [PubMed], [CAS], Google Scholar.224ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE1cXltVSjsr0%253D&md5=383b527f72528e860c4b21f2fdb7fccd9-(2-Hydroxyethoxymethyl)guanine activity against viruses of the herpes groupSchaeffer, H. J.; Beauchamp, Lilia; De Miranda, P.; Elion, Gertrude B.; Bauer, D. J.; Collins, P.Nature (London, United Kingdom) (1978), 272 (5654), 583-5CODEN: NATUAS; ISSN:0028-0836.Of a series of nucleoside analogs synthesized, 9-(2-hydroxyethoxymethyl)guanine (I) [59277-89-3] had marked antiviral activity with low toxicity in animal models of herpes virus infections. In mice the oral and i.p. LD50 values for I were >10,000 and 1000 mg/kg, resp.; no toxicity was obsd. in mice given oral I (450 mg/kg) daily for 30 days. In mice given I, 14C-labeled at the 8-position of the guanine nucleus, 82 and 94% of label was excreted in urine by 4 and 24 h, resp., essentially as unmetabolized I. No appreciable I binding to plasma or tissues was obsd.(b) Faulds, D.; Heel, R. C. Ganciclovir, A review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy in cytomegalovirus infections. Drugs 1990, 39, 597– 638, DOI: 10.2165/00003495-199039040-00008[Crossref], [PubMed], [CAS], Google Scholar224bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3cXksFWqs7g%253D&md5=21f69e930a9cae9afc92f98f615d2b1fGanciclovir: a review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy in cytomegalovirus infectionsFaulds, Diana; Heel, Rennie C.Drugs (1990), 39 (4), 597-638CODEN: DRUGAY; ISSN:0012-6667.A review with 193 refs.
- 225(a) Soul-Lawton, J.; Seaber, E.; On, N.; Wootton, R.; Rolan, P.; Posner, J. Absolute bioavailability and metabolic disposition of valaciclovir, the L-valyl ester of acyclovir, following oral administration to humans. Antimicrob. Agents Chemother. 1995, 39, 2759– 2764, DOI: 10.1128/AAC.39.12.2759[Crossref], [PubMed], [CAS], Google Scholar.225ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXps1Orsbk%253D&md5=bf55e491328feb42e158c4a9626777daAbsolute bioavailability and metabolic disposition of valaciclovir, the L-valyl ester of acyclovir, following oral administration to humansSoul-Lawton, J.; Seaber, E.; On, N.; Wootton, R.; Rolan, P.; Posner, J.Antimicrobial Agents and Chemotherapy (1995), 39 (12), 2759-64CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)Valaciclovir (Valtrex), the L-valyl ester of acyclovir, is undergoing clin. development for the treatment and suppression of herpesviral diseases. The abs. bioavailability of acyclovir from valaciclovir and the metabolic disposition of valaciclovir were investigated with healthy volunteers in two sep. studies. In a randomized, crossover study, 12 fasting healthy volunteers each received 1,000 mg of oral valaciclovir and a 1-h i.v. infusion of 350 mg of acyclovir. The mean abs. bioavailability of acyclovir was 54.2%, a value three to five times that obtained previously with oral acyclovir. A similar est. of 51.3% was made from urinary recovery of acyclovir. In the second study, four fasting volunteers received a single oral dose of 1,000 mg of [14C]valaciclovir. The majority of plasma radioactivity was accounted for by acyclovir, with very low plasma valaciclovir concns. (mean max. concn. of drug in plasma = 0.19 μM0, which were undetectable after 3 h postdose. By 168 h, more than 90% of the administered radioactive dose was recovered, with approx. 46% in urine and 47% in feces. More than 99% of the radioactivity recovered in urine corresponded to acyclovir and its known metabolites, 9-(carboxymethoxymethyl)guainine and 8-hydroxy-9-[(2-hydroxyethoxy)methyl]guanine, with valaciclovir accounting for less than 0.5% of the dose. Acyclovir, but no valaciclovir, was detected in fecal samples. These studies show that after oral administration to humans, valaciclovir is rapidly and virtually completely converted to acyclovir to provide a high level of acyclovir bioavailability in comparison with that following oral administration of acyclovir. The plasma acyclovir exposure obtained following oral administration of valaciclovir is similar to that achieved with doses of i.v. acyclovir, which are effective in the treatment and suppression of the less susceptible herpesviral diseases.(b) Abete, J. F.; Martín-Davila, P.; Moreno, S.; Quijino, Y.; Vicente, E.; Pou, L. Pharmacokinetics of oral valganciclovir and intravenous ganciclovir administered to prevent cytomegalovirus disease in an adult patient receiving small-intestine transplantation. Antimicrob. Agents Chemother. 2004, 48, 2782– 2783, DOI: 10.1128/AAC.48.7.2782-2783.2004[Crossref], [PubMed], [CAS], Google Scholar225bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXlsFWlsr0%253D&md5=e6154602210aa0d5b0b823a133b5a622Pharmacokinetics of oral valganciclovir and intravenous ganciclovir administered to prevent cytomegalovirus disease in an adult patient receiving small-intestine transplantationAbete, Jesus Fortun; Martin-Davila, Pilar; Moreno, S.; Quijano, Yolanda; De Vicente, Emilio; Pou, LeonorAntimicrobial Agents and Chemotherapy (2004), 48 (7), 2782-2783CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)There is no expanded citation for this reference.
- 226(a) de Vrueh, R. L. A.; Smith, P. L.; Lee, C. P. Transport of L-valine-acyclovir via the oligopeptide transporter in the human intestinal cell line, Caco-2. J. Pharmacol. Exp. Ther. 1998, 286, 1166– 1170[PubMed], [CAS], Google Scholar.226ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXmt1Gru70%253D&md5=387fc11bc6d4c9478431e0d3279dd811Transport of L-valine-acyclovir via the oligopeptide transporter in the human intestinal cell line, Caco-2De Vrueh, Remco L. A.; Smith, Philip L.; Lee, Chao-PinJournal of Pharmacology and Experimental Therapeutics (1998), 286 (3), 1166-1170CODEN: JPETAB; ISSN:0022-3565. (Williams & Wilkins)It has been reported that conjugating acyclovir, a potent antiviral with low oral bioavailability, to L-valine increases its urinary excretion in rats. However, it was also reported that this increase is not found for the D-valine ester, suggesting that a carrier-mediated mechanism is involved in its intestinal absorption. Therefore, mechanisms involved in the transepithelial transport of L-valine-acyclovir were investigated using the intestinal cell line, Caco-2, as a model system for the intestinal epithelium. Only the mucosal-to-serosal transport of acyclovir was increased by conjugation with L-valine (∼7-fold), suggesting the involvement of a carrier-mediated mechanism. This conclusion was supported by the finding that this increase was saturable. The mucosal-to-serosal transport of L-valine-acyclovir could be inhibited by L-glycylsarcosine, but not by L-valine, suggesting the involvement of the dipeptide carrier. Also it was found that L-valine-acyclovir inhibits the uptake of cephalexin, a substrate for the oligopeptide transporter. Stability of the esters in either the mucosal or serosal bathing soln. is more than 90% after completion of the transport study. However, after transport, the receiver soln. contained approx. 90% of acyclovir. Based on these findings it was concluded that absorption of the L-valine ester of acyclovir occurs as a result of uptake by the oligopeptide transporter at the apical cell membrane followed by intracellular hydrolysis of the ester and efflux of acyclovir.(b) Han, H. K.; de Vrueh, R. L. A.; Rhie, J. K.; Covitz, K. M. Y.; Smith, P. L.; Lee, C. P.; Oh, D. M.; Sadee, W.; Amidon, G. L. 5′-Amino acid esters of antiviral nucleosides, acyclovir and AZT, are absorbed by the intestinal PEPT1 peptide transporter. Pharm. Res. 1998, 15, 1154– 1159, DOI: 10.1023/A:1011919319810[Crossref], [PubMed], [CAS], Google Scholar.226bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1cXltFynsb4%253D&md5=b370b141aa1747280d117cf07c51a7b25'-Amino acid esters of antiviral nucleosides, acyclovir, and AZT are absorbed by the intestinal PEPT1 peptide transporterHan, Hyo-Kyung; De Vrueh, Remco L. A.; Rhie, Julie K.; Covitz, Kuang-Ming Y.; Smith, Philip L.; Lee, Chao-Pin; Oh, Doo-Man; Sadee, Wolfgang; Amidon, Gordon L.Pharmaceutical Research (1998), 15 (8), 1154-1159CODEN: PHREEB; ISSN:0724-8741. (Plenum Publishing Corp.)General use of nucleoside analogs in the treatment of viral infections and cancer is often limited by poor oral absorption. Valacyclovir, a water sol. amino acid ester prodrug of acyclovir has been reported to increase the oral bioavailability of acyclovir but its absorption mechanism is unknown. This study characterized the intestinal absorption mechanism of 5'-amino acid ester prodrugs of the antiviral drugs and examd. the potential of amino acid esters as an effective strategy for improving oral drug absorption. Acyclovir (ACV) and Zidovudine (AZT) were selected as the different sugar-modified nucleoside antiviral agents and synthesized to L-valyl esters of ACV and AZT (L-Val-ACV and L-Val-AZT), D-valyl ester of ACV (D-Val-ACV) and glycyl ester of ACV (Gly-ACV). The intestinal absorption mechanism of these 5'-amino acid ester prodrugs was characterized in three different exptl. systems: in situ rat perfusion model, CHO/hPEPT1 cells and Caco-2 cells. Testing 5'-amino acid ester prodrugs of acyclovir and AZT, the authors found that the prodrugs increased the intestinal permeability of the parent nucleoside analog 3-to 10-fold. The dose- dependent permeation enhancement was selective for the L-amino acid esters. Competitive inhibition studies in rats and in CHO cells transfected with the human peptide transporter, hPEPT1, demonstrated that membrane transport of the prodrugs was mediated predominantly by the PEPT1 H+ H+/dipeptide cotransporter even though these prodrugs did not possess a peptide bond. Finally, transport studies in Caco-2 cells confirmed that the 5'-amino acid ester prodrugs enhanced the transcellular transport of the parent drug. This study demonstrates that L-amino acid-nucleoside chimeras can serve as prodrugs to enhance intestinal absorption via the PEPT1 transporter, providing a novel strategy for improving oral therapy of nucleoside drugs.(c) Sugawara, M.; Huang, W.; Fei, Y. J.; Leibach, F. H.; Ganapathy, V.; Ganapathy, M. E. Transport of valganciclovir, a ganciclovir prodrug, via peptide transporters PEPT1 and PEPT2. J. Pharm. Sci. 2000, 89, 781– 789, DOI: 10.1002/(SICI)1520-6017(200006)89:6<781::AID-JPS10>3.0.CO;2-7[Crossref], [PubMed], [CAS], Google Scholar226chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXkt1artbY%253D&md5=bff73ba55562df124b08ecdaebcaa8b6Transport of valganciclovir, a ganciclovir prodrug, via peptide transporters PEPT1 and PEPT2Sugawara, Mitsuru; Huang, Wei; Fei, You-Jun; Leibach, Frederick H.; Ganapathy, Vadivel; Ganapathy, Malliga E.Journal of Pharmaceutical Sciences (2000), 89 (6), 781-789CODEN: JPMSAE; ISSN:0022-3549. (Wiley-Liss, Inc.)In clin. trials, valganciclovir, the valyl ester of ganciclovir, has been shown to enhance the bioavailability of ganciclovir when taken orally by patients with cytomegalovirus infection. We investigated the role of the intestinal peptide transporter PEPT1 in this process by comparing the interaction of ganciclovir and valganciclovir with the transporter in different exptl. systems. We also studied the interaction of these two compds. with the renal peptide transporter PEPT2. In cell culture model systems using Caco-2 cells for PEPT1 and SKPT cells for PEPT2, valganciclovir inhibited glycylsarcosine transport mediated by PEPT1 and PEPT2 with Ki values (inhibition const.) of 1.68 ± 0.30 and 0.043 ± 0.005 mM, resp. The inhibition by valganciclovir was competitive in both cases. Ganciclovir did not interact with either transporter. Similar studies done with cloned PEPT1 and PEPT2 in heterologous expression systems yielded comparable results. The transport of valganciclovir via PEPT1 was investigated directly in PEPT1-expressing Xenopus laevis oocytes with an electrophysiol. approach. Valganciclovir, but not ganciclovir, induced inward currents in PEPT1-expressing oocytes. These results demonstrate that the increased bioavailability of valganciclovir is related to its recognition as a substrate by the intestinal peptide transporter PEPT1. This prodrug is also recognized by the renal peptide transporter PEPT2 with high affinity.
- 227(a) Bonvicini, P.; Levi, A.; Lucchini, V.; Modena, G.; Scorrano, G. Acid-base behavior of alkyl sulfur and oxygen bases. J. Am. Chem. Soc. 1973, 95, 5960– 5964, DOI: 10.1021/ja00799a023[ACS Full Text.], [CAS], Google Scholar227ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE3sXlt1GlsbY%253D&md5=2679544e870e3767b49fb41f537f9e65Acid-base behavior of alkyl sulfur and oxygen basesBonvicini, Piero; Levi, Arrigo; Lucchini, Vittorio; Modena, Giorgio; Scorrano, GianfrancoJournal of the American Chemical Society (1973), 95 (18), 5960-4CODEN: JACSAT; ISSN:0002-7863.The acid-base equilibria in H2SO4 solns. of simple dialkyl ethers were evaluated by a NMR technique and compared with results obtained on corresponding sulfides. The pKBH+ values are ∼4 units more positive for ethers than for sulfides. The reasons of different solvation requirements of weak bases are briefly discussed and related to differences in Bunnett and Olsen .vphi. values. The .vphi. values for ethers (∼+0.8) are much greater than for sulfides (∼-0.3). This makes the ionization ratio of sulfides greater than that of ethers at higher acidities, which is related with the order of basicity obsd. in the gas phase (R2S > R2O). Estimation of the basicity of methyl mercaptan and methyl disulfide suggests the basicity scale R2S > R2S2 ≃ RSH, whereas MeOH is found more basic than Me2O.(b) Fife, T. H.; Jao, L. K. The acid-catalyzed hydrolysis of 2-(substituted phenyl)-1,3-oxathiolanes. J. Am. Chem. Soc. 1969, 91, 4217– 4220, DOI: 10.1021/ja01043a034[ACS Full Text], [CAS], Google Scholar227bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaF1MXks1Sgsr0%253D&md5=5267341d3dabc5b3ccebf6b874450f9dAcid-catalyzed hydrolysis of 2-(substituted phenyl)-1,3-oxathiolanesFife, Thomas H.; Jao, L. K.Journal of the American Chemical Society (1969), 91 (15), 4217-20CODEN: JACSAT; ISSN:0002-7863.The rates of acid-catalyzed hydrolysis of a series of 2-(substituted phenyl)-1,3-oxathiolanes were measured in H2O and 50% dioxane-H2O. A plot of the logarithms of the rate consts. vs. σ, the Hammett substituent const., is curved, the point for the p-methoxy-substituted compd. showing considerable pos. deviation from the line established by the use of m-substituted compds. and compds. having electron-withdrawing substituents in the p-position (ρ = -2.8). The p-methoxy group produces neg. deviation when σ+ consts. are employed and H2O is the solvent. Reasonable linearity is obtained, however, with σ+ and the logarithms of rate consts. measured in 50% dioxane-H2O. A plot of log kobsd for hydrolysis of 2-(p-nitrophenyl)-1,3-oxathiolane in various aq. HCl solns. vs. -H0 is linear with a slope of 1.23. Thus, the transition state in these hydrolysis reactions must resemble a carbonium ion with the most likely mechanism involving a unimol. decompn. of a protonated intermediate. The value of kD2O/kH2O for hydrolysis of 2-(p-methoxyphenyl)-1,3-oxathiolane (1.93) is considerably less than normally observed for hydrolysis of analogous acetals and may indicate that the protonated intermediate has S protonated. The value of ΔS* for hydrolysis of 2-phenyl-1,3-oxathiolane is -13.2 entropy units.
- 228Chandrasekhar, S.; Chopra, D.; Gopalaiah, K.; Row, T. The generalized anomeric effect in the 1,3-thiazolidines: Evidence for both sulphur and nitrogen as electron donors. Crystal structures of various N-acylthiazolidines including mercury(II) complexes. Possible relevance to penicillin action. J. Mol. Struct. 2007, 837, 118– 131, DOI: 10.1016/j.molstruc.2006.10.034[Crossref], [CAS], Google Scholar228https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXksVyhs70%253D&md5=d712e761aada8013b860d4f52ae95928The generalized anomeric effect in the 1,3-thiazolidines: Evidence for both sulphur and nitrogen as electron donors. Crystal structures of various N-acylthiazolidines including mercury(II) complexes. Possible relevance to penicillin actionChandrasekhar, Sosale; Chopra, Deepak; Gopalaiah, Kovuru; Guru Row, Tayur N.Journal of Molecular Structure (2007), 837 (1-3), 118-131CODEN: JMOSB4; ISSN:0022-2860. (Elsevier B.V.)Evidence for the generalized anomeric effect (GAE) in the N-acyl-1,3-thiazolidines, an important structural motif in the penicillins, was sought in the crystal structures of N-(4-nitrobenzoyl)-1,3-thiazolidine and its (2:1) complex with mercuric chloride, N-acetyl-2-phenyl-1,3-thiazolidine, and the (2:1) complex of N-benzoyl-1,3-thiazolidine with mercuric bromide. An inverse relationship was generally obsd. between the C2-N and C2-S bond lengths of the thiazolidine ring, supporting the existence of the GAE. (Maximal bond length changes were ∼0.04 Å for C2-N3, S1-C2, and ∼0.08 Å for N3-C6.). Comparison with N-acylpyrrolidines and tetrahydrothiophenes indicates that both the nitrogen-to-sulfur and sulfur-to-nitrogen GAE's operate simultaneously in the 1,3-thiazolidines, the former being dominant. (This is analogous to the normal and exo-anomeric effects in pyranoses, and also leads to an interesting application of Baldwin's rules.). The nitrogen-to-sulfur GAE is generally enhanced in the mercury(II) complexes (presumably via coordination at the sulfur); a competition' between the GAE and the amide resonance of the N-acyl moiety is apparent. There is evidence for a 'push-pull' charge transfer between the thiazolidine moieties in the mercury(II) complexes, and for a 'back-donation' of charge from the bromine atoms to the thiazolidine moieties in the HgBr2 complex. (The sulfur atom appears to be sp2 hybridized in the mercury(II) complexes, possibly for stereoelectronic reasons.). These results are apparently relevant to the mode of action of the penicillins.
- 229Dionne, G. 3TC: a Canadian scientific success story. McGill Journal of Medicine (MJM). 1999, 5, 60– 65
- 230Liotta, D. C.; Painter, G. R. Discovery and development of the anti-human immunodeficiency virus drug, emtricitabine (emtriva, FTC). Acc. Chem. Res. 2016, 49, 2091– 2098, DOI: 10.1021/acs.accounts.6b00274[ACS Full Text], [CAS], Google Scholar230https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhs1SqsrnN&md5=61144ce2d7cc93822a86dc07c0cf8645Discovery and Development of the Anti-Human Immunodeficiency Virus Drug, Emtricitabine (Emtriva, FTC)Liotta, Dennis C.; Painter, George R.Accounts of Chemical Research (2016), 49 (10), 2091-2098CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)The HIV/AIDS epidemic, which was first reported on in 1981, progressed in just ten years to a disease afflicting ten million people worldwide including one million in the US. In 1987 AZT was approved for treating HIV/AIDS. Unfortunately, its clin. usefullness was severly limited by assocd. toxicities and the emergence of resistance. Three other drugs that were approved in the early 1990s suffered from similar liabilities. In 1990 the Liotta group at Emory University developed a highly diastereoselective synthesis of racemic 3'-thia-2',3'-dideoxycytidine and 3'-thia-2',3'-5-fluorodideoxycytidine and demonstrated that these compds. exhibited excellent anti-HIV activity with no apparent cytotoxicity. Subsequently, the enantiomers of these compds. were sepd. using enzyme-mediated kinetic resolns. and their (-)-enantiomers (3TC and FTC, resp.) were found to have exceptionally attractive preclin. profile. In addn. to their anti-HIV activity, 3TC and FTC potently inhibited the replication of hepatitis B virus. The development of FTC, which was being carried out by Burroughs Wellcome, had many remarkable starts and stops. For example, passage studies indicated that the compd. rapidly selected for a single resistant mutant, M184 V, and that this strain was 500-1000 fold less sensitive to FTC than was wild type virus. Fortunately, it was found that combinations of AZT with either 3TC or FTC were synergistic with AZT. The effectiveness of AZT-3TC combination therapy was subsequently demonstrated in four independent clin. trials and in 1997 the FDA approved Combivir, a fixed dose combination of AZT and 3TC. In Phase 1 clin. trials FTC was well tolerated by all subjects with no adverse events obsd. However, the development of FTC was halted by the aquistition of Wellcome PLC by Glaxo PLC in Jan., 1995. In 1996 Triangle Pharmaceuticals licensed FTC from Emory and initiated a series of Phase I/II clin. studies that demonstrated the safety and efficacy of the drug. In August, 1998 FTC was granted "Fast Track" status, based primarily on its potential for once daily dosing. While the outcomes of two subsequent Phase III trials were pos., a third Phase III clin. trial involving combinations of 3TC or FTC with stavudine and neviripine had to be terminated due to serious liver-related adverse events. Although anal. of the data suggested that the liver toxicity was due to neviripine, the FDA decided that the study could not be used for drug registration. Ultimately, in Jan., 2003 Gilead Sciences acquired Triangle Pharmaceuticals and completed the development of FTC (emtricitabine), which was approved for once a day, oral administration in July, 2003. A year later, Truvada, a once a day, oral, fixed dose combination of emtricitabine and tenofovir disoproxyl fumarate received FDA approval and quickly became the accepted first line therapy when used with a third antiretroviral agent. In July, 2006 the FDA approved Atripla, a once a day, oral, fixed dose combination of emtricitabine, tenofovir disoproxyl fumarate and efavirenz, which represented the culmination of two decades of research that had transformed AIDS from a death sentence to a manageable chronic disease.
- 231(a) Gumina, G.; Song, G.; Chu, C. K. L-Nucleosides as chemotherapeutic agents. FEMS Microbiol. Lett. 2001, 202, 9– 15, DOI: 10.1016/S0378-1097(01)00285-3[Crossref], [PubMed], [CAS], Google Scholar.231ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXlvFWlurw%253D&md5=6882b91a21ba60c920b0af1cbeefb5d8L-Nucleosides as chemotherapeutic agentsGumina, G.; Song, G.-Y.; Chu, C. K.FEMS Microbiology Letters (2001), 202 (1), 9-15CODEN: FMLED7; ISSN:0378-1097. (Elsevier Science B.V.)A review with refs. Nucleoside analogs have been the cornerstone of antiviral therapy over the past thirty years and, currently, 16 commonly used antiviral drugs belong to this category. Although for long time it was believed that only D-nucleosides, possessing a 'natural' stereochem., could elicit biol. activity, in the last decade this has been proven not to be true. 3TC, a L-nucleoside analog, is one of the most effective anti-HIV and anti-hepatitis B virus drugs, and nine other L-nucleosides are currently undergoing clin. trials and/or preclin. studies as antiviral or antitumoral agents. This article summarizes some biol. features and the current status of these promising L-nucleoside analogs.(b) Kim, H. O.; Shanmuganatban, K.; Alves, A. J.; Jeong, L. S.; Beacb, J. W.; Schinazi, R. F.; Chang, C.; Cheng, Y.; Chu, C. K. Potent anti-HIV and anti-HBV activities of (−)-L-β-dioxolane-C and (+)-L-β-dioxolane-T and their asymmetric syntheses. Tetrahedron Lett. 1992, 33, 6899– 6902, DOI: 10.1016/S0040-4039(00)60890-0[Crossref], [CAS], Google Scholar231bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3sXmtVSgsg%253D%253D&md5=3a52b8a12f67ab3ee751b0ba1141493ePotent anti-HIV and anti-HBV activities of (-)-L-β-dioxolane-C and (+)-L-β-dioxolane-T and their asymmetric synthesesKim, Hea O.; Shanmuganathan, Kirupathevy; Alves, Antonio J.; Jeong, Lak S.; Beach, J. Warren; Schinazi, Raymond F.; Chang, Chien Neng; Cheng, Yung Chi; Chu, Chung K.Tetrahedron Letters (1992), 33 (46), 6899-902CODEN: TELEAY; ISSN:0040-4039.The asym. syntheses of (+)-L-β-dioxolane-T (I; R = Me, R1 = OH) and (-)-L-β-dioxolane-C (I; R= H, R1 = NH2) were accomplished starting from 1,6-anhydro-L-β-gulopyranose (II), and their anti-HIV and anti-HBV activities were evaluated in human PBM cells, CEM cells and 2.2.15 cells, resp.
- 232(a) Grove, K. L.; Guo, X.; Liu, S.-H.; Gao, Z.; Chu, C. K.; Cheng, Y.-C. Anticancer activity of β-l-dioxolane-cytidine, a novel nucleoside analogue with the unnatural L configuration. Cancer Res. 1995, 55, 3008– 3011[PubMed], [CAS], Google Scholar.232ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXmvVyitr0%253D&md5=af0bf83131a7ce02e0579e7209de92d5Anticancer activity of β-L-dioxolane-cytidine, a novel nucleoside analog with the unnatural L configurationGrove, Kristie L.; Guo, Xin; Liu, Shwu-Huey; Gao, Zhiling; Chu, Chung K.; Cheng, Yung-ChiCancer Research (1995), 55 (14), 3008-11CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)Naturally occurring nucleosides and all anticancer nucleoside analog drugs are in the β-D-configuration. L-(-)-Dioxolane-cytidine [(-)-OddC] is the first L-nucleotide analog ever shown to have anticancer activity. This compd. was converted within cells to its mono-, di-, and triphosphatate metabolites and was incorporated into DNA. As with cytosine arabinoside, conversion to the monophosphate was catalyzed by cellular deoxycytidine kinase, which was essential for cytotoxicity. However, unlike cytosine arabinoside, (-)-OddC was not susceptible to degrdn. by deoxycytidine deaminase. Because (-)-OddC inhibited the growth of hepatocellular and prostate tumors that are generally difficult to treat, it is a promising candidate for addnl. testing. Our results indicate that there is a great deal of variability in the chiral specificities of cellular enzymes and demonstrate how these differences can be exploited in the design of better anti-viral and anticancer drugs.(b) Lapointe, R.; Letourneau, R.; Steward, W.; Hawkins, R. E.; Batist, G.; Vincent, M.; Whittom, R.; Eatock, M.; Jolivet, J.; Moore, M. Phase II study of troxacitabine in chemotherapy-naïve patients with advanced cancer of the pancreas. Annals Oncol. 2005, 16, 289– 293, DOI: 10.1093/annonc/mdi061[Crossref], [PubMed], [CAS], Google Scholar.232bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2M%252FjvFyhsQ%253D%253D&md5=4d7e4af461cc462cb7977cdda1bc9b3aPhase II study of troxacitabine in chemotherapy-naive patients with advanced cancer of the pancreas: gastrointestinal tumorsLapointe R; Letourneau R; Steward W; Hawkins R E; Batist G; Vincent M; Whittom R; Eatock M; Jolivet J; Moore MAnnals of oncology : official journal of the European Society for Medical Oncology (2005), 16 (2), 289-93 ISSN:0923-7534.BACKGROUND: Troxacitabine (Troxatyl) is a novel L-enantiomer nucleoside analog with activity in pancreatic cancer xenograft models. PATIENTS AND METHODS: Troxacitabine 1.5 mg/m(2) was administered by 30-min infusions daily x5 every 4 weeks to 54 patients with advanced pancreatic cancer. Patients were evaluated for objective tumor response, time to tumor progression (TTP), changes in tumor marker CA 19-9, survival, safety, pain, analgesic consumption, Karnofsky performance status and weight change. RESULTS: Median TTP was 3.5 months (95% CI 2.0-3.8), median survival 5.6 months (95% CI 4.9-7.4), and the 1 year survival rate 19%. Best responses were stable disease in 24 patients with eight patients having stable disease for at least 6 months (15%). A 50% or greater decrease in CA 19-9 was seen in seven of 44 assessed patients (16%). Grade 3 and 4 neutropenia were observed in 37% and 30% of patients with one episode of febrile neutropenia. The most common drug-related non-hematological toxic effects reported were cutaneous, with 22% and 6% of patients reporting grade 2 and 3 skin rash, respectively and 4% grade 2 hand-foot syndrome. CONCLUSION: Troxacitabine administered by a bolus daily x5 monthly regimen has modest activity in advanced pancreatic adenocarcinoma.(c) Moore, L. E.; Boudinot, F. D.; Chu, C. K. Preclinical pharmacokinetics of β-L-dioxolane-cytidine, a novel anticancer agent, in rats. Cancer Chemother. Pharmacol. 1997, 39, 532– 536, DOI: 10.1007/s002800050609[Crossref], [PubMed], [CAS], Google Scholar.232chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXis1ajt74%253D&md5=f375e2216ad2f285caac69f120157705Preclinical pharmacokinetics of β-L-dioxolane-cytidine, a novel anticancer agent, in ratsMoore, Laura E.; Boudinot, F. Douglas; Chu, Chung K.Cancer Chemotherapy and Pharmacology (1997), 39 (6), 532-536CODEN: CCPHDZ; ISSN:0344-5704. (Springer)Following i.v. administration, the plasma concns. of β-L-dioxolane-cytidine (OddC) declined in a biexponential manner with a terminal phase half-life of 1.65 h. Total, renal, and nonrenal clearances were 1.38, 0.30 and 1.08 1/h per kg, resp. Nonrenal clearance was the predominant route of elimination of OddC because 22% of the administered dose was excreted unchanged in the urine. The steady-state vol. of distribution averaged 1.42 l/kg. The nucleoside analog was slowly absorbed after oral administration and bioavailability varied. The pharmacokinetics of OddC in rats were linear over the dose range studied.(d) Swords, R.; Giles, F. Troxacitabine in acute leukemia. Hematology 2007, 12, 219– 227, DOI: 10.1080/10245330701406881[Crossref], [PubMed], [CAS], Google Scholar232dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXmt1ans70%253D&md5=8a51b2b084e37c7500b5568973f5c3d5Troxacitabine in acute leukemiaSwords, R.; Giles, F.Hematology (London, United Kingdom) (2007), 12 (3), 219-227CODEN: HMATFL; ISSN:1024-5332. (Informa Healthcare)A review. Troxacitabine (Troxatyl; BCH-4556; (-)-2'-deoxy-3'-oxacytadine) is the first synthetic L-nucleoside enantiomer to demonstrate broad spectrum cytotoxic activity. It was obtained by exchanging the sulfur endocyclic atom with oxygen in the structure of lamivudine, following the discovery that this agent had cytotoxic, as well as anti-viral activity. The unique "unnatural" stereochem. of troxacitabine has produced impressive cytotoxic potency against a wide range of malignancies in the lab. which led to its selection for clin. development. The initial trials with troxacitabine have established its efficacy in both solid and haematol. malignancies, including those resistant to ara-C (cytarabine). This review will consider troxacitabine in terms of its pharmacol., mode of action, pharmacokinetics, tolerability and clin. efficacy.
- 233Lin, J.; Kira, T.; Gullen, E.; Choi, Y.; Qu, F.; Chu, C. K.; Cheng, Y. Structure-activity relationships of L-dioxolane uracil nucleosides as anti-Epstein Barr virus agents. J. Med. Chem. 1999, 42, 2212– 2217, DOI: 10.1021/jm9806749[ACS Full Text], [CAS], Google Scholar233https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK1MXjt1aqsrc%253D&md5=11f185e3b77be0c05d322c689edcee7bStructure-Activity Relationships of L-Dioxolane Uracil Nucleosides as Anti-Epstein Barr Virus AgentsLin, Ju-Sheng; Kira, Toshihiko; Gullen, Elizabeth; Choi, Yongseok; Qu, Fucheng; Chu, Chung K.; Cheng, Yung-ChiJournal of Medicinal Chemistry (1999), 42 (12), 2212-2217CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A series of 1,3-dioxolanyluracil analogs was prepd. from the dioxolane intermediates and their anti-Epstein Barr virus (anti-EBV) activities were detd. The potency of L-dioxolane uracil nucleosides against EBV replication is dependent on the substituents at the 5-position in the following decreasing order: I > Br > Cl > CH3 > CF3 > F. The most active and selective analog was the iodo deriv. (L-I-OddU) with an EC50 value of 0.03 μM and an EC90 value of 0.16 μM. There was no cytotoxicity or depletion of mitochondrial DNA in cells after exposure to L-I-OddU at 50 μM. The action against EBV replication in H1 cells is time-dependent, and EBV DNA in cells treated with L-I-OddU could rebound to pretreatment levels once the drug was removed. In view of the potent antiviral activity plus favorable toxicity profiles, L-I-OddU may be potentially useful for the treatment of EBV-related infectious diseases as well as for delaying the onset or decreasing the incidence of EBV-assocd. cancers.
- 234Liang, C.; Lee, D. W.; Newton, M. G.; Chu, C. K. Synthesis of L-dioxolane nucleosides and related chemistry. J. Org. Chem. 1995, 60, 1546– 1553, DOI: 10.1021/jo00111a012[ACS Full Text], [CAS], Google Scholar234https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXktlemu78%253D&md5=8dd8cfd960a6749fba35492429e955acSynthesis of L-Dioxolane Nucleosides and Related ChemistryLiang, Chengyi; Lee, Doo Won; Newton, M. Gary; Chu, Chung K.Journal of Organic Chemistry (1995), 60 (6), 1546-53CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)Hydroxymethyldioxolanylfluorouracil I and other novel classes of 1,3-dioxolane nucleosides have been synthesized. Coupling of 2-methoxy-4-[[(tert-butyldiphenylsilyl)oxy]methyl]-1,3-dioxolane (23) or 2-methyl-1,3-dioxolane (9) with silylated 5-fluorouracil, thymine, cytosine, and 5-chlorocytosine in the presence of TMSOTf gave the corresponding 1,3-dioxolane nucleosides. These nucleosides were decompd. and rearranged to the ring-opened products in certain reaction conditions. It was found that 5-fluorouracil nucleosides (12 and 25) were relatively more stable than the thymine or cytosine derivs. (10, 13, and 16). Bulky protecting group (TBDPS) at the 1,3-dioxolane moiety in compd. 24 may also contribute the stability to the 1,3-dioxolane nucleosides. The structures of these novel 1,3-dioxolane nucleosides and ring-opened products have been assigned by NMR spectra, and the mechanisms of decompn. and rearrangement to the ring opened products were discussed.
- 235(a) Goodwin, N. C.; Mabon, R.; Harrison, B. A.; Shadoan, M. K.; Almstead, Z. Y.; Xie, Y.; Healy, J.; Buhring, L. M.; DaCosta, C. M.; Bardenhagen, J.; Mseeh, F.; Liu, Q.; Nouraldeen, A.; Wilson, A. G.; Kimball, D.; Powell, D. R.; Rawlins, D. B. Novel L-xylose derivatives as selective sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors for the treatment of type 2 diabetes. J. Med. Chem. 2009, 52, 6201– 6204, DOI: 10.1021/jm900951n[ACS Full Text.], [CAS], Google Scholar235ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtF2ltb3O&md5=120dfc29a33db5857cb6876b35b9edf4Novel L-Xylose Derivatives as Selective Sodium-Dependent Glucose Cotransporter 2 (SGLT2) Inhibitors for the Treatment of Type 2 DiabetesGoodwin, Nicole C.; Mabon, Ross; Harrison, Bryce A.; Shadoan, Melanie K.; Almstead, Zheng Y.; Xie, Yiling; Healy, Jason; Buhring, Lindsey M.; DaCosta, Christopher M.; Bardenhagen, Jennifer; Mseeh, Faika; Liu, Qingyun; Nouraldeen, Amr; Wilson, Alan G. E.; Kimball, S. David; Powell, David R.; Rawlins, David B.Journal of Medicinal Chemistry (2009), 52 (20), 6201-6204CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The prevalence of diabetes throughout the world continues to increase and has become a major health issue. Recently there have been several reports of inhibitors directed toward the sodium-dependent glucose cotransporter 2 (SGLT2) as a method of maintaining glucose homeostasis in diabetic patients. Herein we report the discovery of the novel O-xyloside 7c (I) that inhibits SGLT2 in vitro and urinary glucose reabsorption in vivo.(b) Goodwin, N. C.; Ding, Z.; Harrison, B. A.; Strobel, E. D.; Harris, A. L.; Smith, M.; Thompson, A. Y.; Xiong, W.; Mseeh, F.; Bruce, D. J.; Diaz, D.; Gopinathan, S.; Li, L.; O’Neill, E.; Thiel, M.; Wilson, A. G.; Carson, K. G.; Powell, D. R.; Rawlins, D. B. Discovery of LX2761, a sodium-dependent glucose cotransporter 1 (SGLT1) inhibitor restricted to the intestinal lumen, for the treatment of diabetes. J. Med. Chem. 2017, 60, 710– 721, DOI: 10.1021/acs.jmedchem.6b01541[ACS Full Text], [CAS], Google Scholar235bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXis1yqtA%253D%253D&md5=d07c28561e0bb9be4320391a94020d5cDiscovery of LX2761, a Sodium-Dependent Glucose Cotransporter 1 (SGLT1) Inhibitor Restricted to the Intestinal Lumen, for the Treatment of DiabetesGoodwin, Nicole C.; Ding, Zhi-Ming; Harrison, Bryce A.; Strobel, Eric D.; Harris, Angela L.; Smith, Melinda; Thompson, Andrea Y.; Xiong, Wendy; Mseeh, Faika; Bruce, Debra J.; Diaz, Damaris; Gopinathan, Suma; Li, Ling; O'Neill, Emily; Thiel, Mary; Wilson, Alan G. E.; Carson, Kenneth G.; Powell, David R.; Rawlins, David B.Journal of Medicinal Chemistry (2017), 60 (2), 710-721CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The increasing no. of people afflicted with diabetes throughout the world is a major health issue. Inhibitors of the sodium-dependent glucose cotransporters (SGLT) have appeared as viable therapeutics to control blood glucose levels in diabetic patients. Herein the authors report the discovery of LX2761, a locally-acting SGLT1 inhibitor that is highly potent in vitro and delays intestinal glucose absorption in vivo to improve glycemic control.
- 236Fioretto, P.; Zambon, A.; Rossato, M.; Busetto, L.; Vettor, R. SGLT2 inhibitors and the diabetic kidney. Diabetes Care 2016, 39, S165– S171, DOI: 10.2337/dcS15-3006[Crossref], [PubMed], [CAS], Google Scholar236https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsFeltLvJ&md5=0be3a707129e0c3fec0f6950b0ad28beSGLT2 inhibitors and the diabetic kidneyFioretto, Paola; Zambon, Alberto; Rossato, Marco; Busetto, Luca; Vettor, RobertoDiabetes Care (2016), 39 (Suppl. 2), S165-S171CODEN: DICAD2; ISSN:0149-5992. (American Diabetes Association, Inc.)Diabetic nephropathy (DN) is the most common cause of end-stage renal disease worldwide. Blood glucose and blood pressure control reduce the risk of developing this complication; however, once DN is established, it is only possible to slow progression. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, the most recent glucose-lowering oral agents, may have the potential to exert nephroprotection not only through improving glycemic control but also through glucose-independent effects, such as blood pressure-lowering and direct renal effects. It is important to consider, however, that in patients with impaired renal function, given their mode of action, SGLT2 inhibitors are less effective in lowering blood glucose. In patients with high cardiovascular risk, the SGLT2 inhibitor empagliflozin lowered the rate of cardiovascular events, esp. cardiovascular death, and substantially reduced important renal outcomes. Such benefits on DN could derive from effects beyond glycemia. Glomerular hyperfiltration is a potential risk factor for DN. In addn. to the activation of the renin-angiotensin-aldosterone system, renal tubular factors, including SGLT2, contribute to glomerular hyperfiltration in diabetes. SGLT2 inhibitors reduce sodium reabsorption in the proximal tubule, causing, through tubuloglomerular feedback, afferent arteriole vasoconstriction and redn. in hyperfiltration. Exptl. studies showed that SGLT2 inhibitors reduced hyperfiltration and decreased inflammatory and fibrotic responses of proximal tubular cells. SGLT2 inhibitors reduced glomerular hyperfiltration in patients with type 1 diabetes, and in patients with type 2 diabetes, they caused transient acute redns. in glomerular filtration rate, followed by a progressive recovery and stabilization of renal function. Interestingly, recent studies consistently demonstrated a redn. in albuminuria. Although these data are promising, only dedicated renal outcome trials will clarify whether SGLT2 inhibitors, in addn. to their glycemic and blood pressure benefits, may provide nephroprotective effects.
- 237(a) Selnick, H. G.; Hess, J. F.; Tang, C.; Liu, K.; Schachter, J. B.; Ballard, J. E.; Marcus, J.; Klein, D. J.; Wang, X.; Pearson, M.; Savage, M. J.; Kaul, R.; Li, T.-S.; Vocadlo, D. J.; Zhou, Y.; Zhu, Y.; Mu, C.; Wang, Y.; Wei, Z.; Bai, C.; Duffy, J. L.; McEachern, E. J. Discovery of MK-8719, a potent O-GlcNAcase inhibitor as a potential treatment for tauopathies. J. Med. Chem. 2019, 62, 10062– 10097, DOI: 10.1021/acs.jmedchem.9b01090[ACS Full Text.], [CAS], Google Scholar237ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhslWms73F&md5=79e26635e124c90c86d4c1beb8b63e23Discovery of MK-8719, a potent O-GlcNAcase inhibitor as a potential treatment for tauopathiesSelnick, Harold G.; Hess, J. Fred; Tang, Cuyue; Liu, Kun; Schachter, Joel B.; Ballard, Jeanine E.; Marcus, Jacob; Klein, Daniel J.; Wang, Xiaohai; Pearson, Michelle; Savage, Mary J.; Kaul, Ramesh; Li, Tong-Shuang; Vocadlo, David J.; Zhou, Yuanxi; Zhu, Yongbao; Mu, Changwei; Wang, Yaode; Wei, Zhongyong; Bai, Chang; Duffy, Joseph L.; McEachern, Ernest J.Journal of Medicinal Chemistry (2019), 62 (22), 10062-10097CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Inhibition of O-GlcNAcase (OGA) has emerged as a promising therapeutic approach to treat tau pathol. in neurodegenerative diseases such as Alzheimer's disease and progressive supranuclear palsy. Beginning with carbohydrate-based lead mols., we pursued an optimization strategy of reducing polar surface area to align the desired drug-like properties of potency, selectivity, high central nervous system (CNS) exposure, metabolic stability, favorable pharmacokinetics, and robust in vivo pharmacodynamic response. Herein, we describe the medicinal chem. and pharmacol. studies that led to the identification of (3aR,5S,6S,7R,7aR)-5-(difluoromethyl)-2-(ethylamino)-3a,6,7,7a-tetrahydro-5H-pyrano[3,2-d]thiazole-6,7-diol 42 (MK-8719), a highly potent and selective OGA inhibitor with excellent CNS penetration that has been advanced to first-in-human phase I clin. trials.(b) Wang, X.; Li, W.; Marcus, J.; Pearson, M.; Song, L.; Smith, K.; Terracina, G.; Lee, J.; Hong, K. K.; Lu, S. X.; Hyde, L.; Chen, S. C.; Kinsley, D.; Melchor, J. P.; Rubins, D. J.; Meng, X.; Hostetler, E.; Sur, C.; Zhang, L.; Schachter, J. B.; Hess, J. F.; Senick, H. G.; Vocadlo, D. J.; McEachern, E. J.; Uslaner, J. M.; Duffy, J. L.; Smith, S. M. MK-8719, a novel and selective O-GlcNAcase inhibitor that reduces the formation of pathological tau and ameliorates neurodegeneration in a mouse model of tauopathy. J. Pharmacol. Exp. Ther. 2020, 374, 252– 263, DOI: 10.1124/jpet.120.266122[Crossref], [PubMed], [CAS], Google Scholar237bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhs1ant7rO&md5=6bc4d898d769945b29816591605d7f91MK-8719, a novel and selective O-GlcNAcase inhibitor that reduces the formation of pathological tau and ameliorates neurodegeneration in a mouse model of tauopathyWang, Xiaohai; Li, Wenping; Marcus, Jacob; Pearson, Michelle; Song, Lixin; Smith, Karen; Terracina, Giuseppe; Lee, Julie; Hong, Kwok-Lam Karen; Lu, Sherry X.; Hyde, Lynn; Chen, Shu-Cheng; Kinsley, David; Melchor, Jerry P.; Rubins, Daniel J.; Meng, Xiangjun; Hostetler, Eric; Sur, Cyrille; Zhang, Lili; Schachter, Joel B.; Hess, J. Fred; Selnick, Harold G.; Vocadlo, David J.; McEachern, Ernest J.; Uslaner, Jason M.; Duffy, Joseph L.; Smith, Sean M.Journal of Pharmacology and Experimental Therapeutics (2020), 374 (2), 252-263CODEN: JPETAB; ISSN:1521-0103. (American Society for Pharmacology and Experimental Therapeutics)Deposition of hyperphosphorylated and aggregated tau protein in the central nervous system is characteristic of Alzheimer disease and other tauopathies. Tau is subject to O-linked N-acetylglucosamine (O-GlcNAc) modification, and O-GlcNAcylation of tau has been shown to influence tau phosphorylation and aggregation. Inhibition of O-GlcNAcase (OGA), the enzyme that removes O-GlcNAc moieties, is a novel strategy to attenuate the formation of pathol. tau. Here we described the in vitro and in vivo pharmacol. properties of a novel and selective OGA inhibitor, MK-8719. In vitro, this compd. is a potent inhibitor of the human OGA enzyme with comparable activity against the corresponding enzymes from mouse, rat, and dog. In vivo, oral administration of MK-8719 elevates brain and peripheral blood mononuclear cell O-GlcNAc levels in a dose-dependent manner. In addn., positron emission tomog. imaging studies demonstrate robust target engagement of MK-8719 in the brains of rats and rTg4510 mice. In the rTg4510 mouse model of human tauopathy, MK-8719 significantly increases brain O-GlcNAc levels and reduces pathol. tau. The redn. in tau pathol. in rTg4510 mice is accompanied by attenuation of brain atrophy, including redn. of forebrain vol. loss as revealed by volumetric magnetic resonance imaging anal. These findings suggest that OGA inhibition may reduce tau pathol. in tauopathies. However, since hundreds of O-GlcNAcylated proteins may be influenced by OGA inhibition, it will be crit. to understand the physiol. and toxicol. consequences of chronic O-GlcNAc elevation in vivo.
- 238Passioura, T.; Watashi, K.; Fukano, K.; Shimura, S.; Saso, W.; Morishita, R.; Ogasawara, Y.; Tanaka, Y.; Mizokami, M.; Sureau, C.; Suga, H.; Wakita, T. De novo macrocyclic peptide inhibitors of hepatitis B virus cellular entry. Cell Chem. Biol. 2018, 25, 906– 915, DOI: 10.1016/j.chembiol.2018.04.011[Crossref], [PubMed], [CAS], Google Scholar238https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXpvVemsL4%253D&md5=abb5f4c3bae8a692b7153546e520f218De Novo Macrocyclic Peptide Inhibitors of Hepatitis B Virus Cellular EntryPassioura, Toby; Watashi, Koichi; Fukano, Kento; Shimura, Satomi; Saso, Wakana; Morishita, Ryo; Ogasawara, Yuki; Tanaka, Yasuhito; Mizokami, Masashi; Sureau, Camille; Suga, Hiroaki; Wakita, TakajiCell Chemical Biology (2018), 25 (7), 906-915.e5CODEN: CCBEBM; ISSN:2451-9448. (Cell Press)Hepatitis B virus (HBV) constitutes a significant public health burden, and currently available treatment options are not generally curative, necessitating the development of new therapeutics. Here we have applied random non-std. peptide integrated discovery (RaPID) screening to identify small macrocyclic peptide inhibitors of HBV entry that target the cell-surface receptor for HBV, sodium taurocholate cotransporting polypeptide (NTCP). In addn. to their anti-HBV activity, these mols. also inhibit cellular entry by the related hepatitis D virus (HDV), and are active against diverse strains of HBV (including clin. relevant nucleos(t)ide analog-resistant and vaccine escaping strains). Importantly, these macrocyclic peptides, in contrast to other NTCP-binding HBV entry inhibitors, exhibited no inhibition of NTCP-mediated bile acid uptake, making them appealing candidates for therapeutic development.
- 239Liu, Y.; Ruan, H.; Li, Y.; Sun, G.; Liu, X.; He, W.; Mao, F.; He, M.; Yan, L.; Zhong, G.; Yan, H.; Li, W.; Zhang, Z. Potent and specific inhibition of NTCP-mediated HBV/HDV infection and substrate transporting by a novel, oral-available cyclosporine a analogue. J. Med. Chem. 2021, 64, 543– 565, DOI: 10.1021/acs.jmedchem.0c01484[ACS Full Text], [CAS], Google Scholar239https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXislShsrzE&md5=d482e6421e8673bab71f255138cdc3fcPotent and Specific Inhibition of NTCP-Mediated HBV/HDV Infection and Substrate Transporting by a Novel, Oral-Available Cyclosporine A AnalogueLiu, Yang; Ruan, Hanying; Li, Ying; Sun, Guoliang; Liu, Xiao; He, Wenhui; Mao, Fengfeng; He, Miaomiao; Yan, Liwei; Zhong, Guocai; Yan, Huan; Li, Wenhui; Zhang, ZhiyuanJournal of Medicinal Chemistry (2021), 64 (1), 543-565CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Analogs of the natural product cyclosporine A (CsA) were developed and assessed as antivirals against infection of hepatitis B virus (HBV) and its satellite hepatitis D virus (HDV). An analog termed 27A exhibits potent inhibition of HBV/HDV infection by specifically blocking viral engagement to its cellular receptor NTCP, while it lacks immunosuppressive activity found in natural CsA. I.p. injection or oral intake of 27A protects HDV-susceptible mouse model from HDV infection. 27A serves as a promising lead for the development of novel anti-HDV/HBV agents.
- 240(a) Satchell, D. P. N.; Satchell, R. S. Mechanisms of hydrolysis of thioacetals. Chem. Soc. Rev. 1990, 19, 55– 81, DOI: 10.1039/cs9901900055[Crossref], [CAS], Google Scholar.240ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3cXkslOgtr4%253D&md5=49ba4e9e2bbc2532f12ca6a4693fc4f1Mechanisms of hydrolysis of thioacetalsSatchell, Derek P. N.; Satchell, Rosemary S.Chemical Society Reviews (1990), 19 (1), 55-81CODEN: CSRVBR; ISSN:0306-0012.This review classifies acetals as either O,O-, O,S-, or S,S compds., and uses the name acetal to subsume ketals; 62 refs.(b) Ali, M.; Satchell, D. P. N. Kinetics and mechanism of hydrolysis of open-chain thioacetals derived from benzophenone and the reactivity of α-thiophenyl carbocations. J. Chem. Soc., Perkin Trans. 2 1995, 167– 170, DOI: 10.1039/P29950000167[Crossref], [CAS], Google Scholar240bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXjtFCqt70%253D&md5=eef4999fe54702f9e1e131515bde9ec4Kinetics and mechanism of hydrolysis of open-chain thioacetals derived from benzophenone and the reactivity of α-thiophenyl carbocationsAli, Muhammad; Satchell, Derek P. N.Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1995), (1), 167-70CODEN: JCPKBH; ISSN:0300-9580. (Royal Society of Chemistry)In a 40% (vol./vol.) dioxane-water solvent, in the presence of 0.3-4.0 mol dm-3 perchloric acid, the rates of hydrolysis of di-Et and di-Ph thioacetals derived from substituted benzophenones exhibit substituent effects, acidity dependencies, activation parameters and solvent isotope effects which all suggest that the hydrolyses follow the A1 mechanism. The di-Et thioacetals are ca. 104-fold less reactive than their O,O-analogs and ca. 104-fold more reactive than the corresponding dithanes, for both of which classes of acetal the ASE2 mechanism of hydrolysis has been suggested. In concd. aq. perchloric acid the diaryl thioacetals are, like the di-Et compds., rapidly and quant. converted into the corresponding α-thio carbocations, which then undergo slow hydrolysis to the benzophenone. Kinetic measurements show that the α-thiophenyl carbocation Ph2C+-SPh is ca. 20-fold more reactive towards hydrolysis than is Ph2C+-SEt, but that substituents in the thiophenyl group have little effect on reactivity (ρ ≃ 0.6). The detailed kinetic results are compatible with our previous suggestions about the mechanism of hydrolysis of α-thio carbocations.
- 241Burghardt, T. E. Developments in the deprotection of thioacetals. J. Sulfur Chem. 2005, 26, 411– 427, DOI: 10.1080/17415990500195198[Crossref], [CAS], Google Scholar241https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XkvFygtw%253D%253D&md5=d74a20de8f93b527e67b7b9be0ce771dDevelopments in the deprotection of thioacetalsBurghardt, T. E.Journal of Sulfur Chemistry (2005), 26 (4-5), 411-427CODEN: JSCOFC; ISSN:1741-5993. (Taylor & Francis Ltd.)A review. Dithioacetals are very important and commonly used protecting groups for carbonyl compds. Among the advantages of their use are the ease of formation, stability under both acidic and basic conditions, and umpolung reactivity. Unfortunately, their deprotection into the corresponding carbonyls is quite often difficult and requires special conditions. Hence, numerous protocols for the dithiane deprotection were devised. In this review, various methodologies that were developed for the hydrolysis of thioacetal protecting groups are summarized and the detailed reaction conditions are presented.
- 242Cushman, D. W.; Ondetti, M. A. Personal and historical perspectives. History of the design of captopril and related inhibitors of angiotensin converting enzyme. Hypertension 1991, 17, 589– 592, DOI: 10.1161/01.HYP.17.4.589[Crossref], [PubMed], [CAS], Google Scholar242https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK3M7pt12jtg%253D%253D&md5=f58df34650d294b90336cef9fb37d76dHistory of the design of captopril and related inhibitors of angiotensin converting enzymeCushman D W; Ondetti M AHypertension (Dallas, Tex. : 1979) (1991), 17 (4), 589-92 ISSN:0194-911X.There is no expanded citation for this reference.
- 243Patchett, A. A. Excursions in drug discovery. J. Med. Chem. 1993, 36, 2051– 2058, DOI: 10.1021/jm00067a001[ACS Full Text], [CAS], Google Scholar243https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3sXkslWku7w%253D&md5=99aa7c812225a933a9a311d31d6033a7Excursions in drug discoveryPatchett, Arthur A.Journal of Medicinal Chemistry (1993), 36 (15), 2051-8CODEN: JMCMAR; ISSN:0022-2623.The E. B. Herschberg Award Address of Arthur A. Patchett is given in honor of his contributions in the design of the antihypertensive drugs enalapril and lisinopril and the discovery of the cholesterol-lowering drug lovastatin.
- 244Smith, E. M.; Swiss, G. F.; Neustadt, B. R.; McNamara, P.; Gold, E. H.; Sybertz, E. J.; Baum, T. Angiotensin converting enzyme inhibitors: spirapril and related compounds. J. Med. Chem. 1989, 32, 1600– 1606, DOI: 10.1021/jm00127a033[ACS Full Text], [CAS], Google Scholar244https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1MXlsFCgtb8%253D&md5=6d8ae032a33b98aade4b6b58291524abAngiotensin converting enzyme inhibitors: spirapril and related compoundsSmith, Elizabeth M.; Swiss, Gerald F.; Neustadt, Bernard R.; McNamara, Paul; Gold, Elijah H.; Sybertz, Edmund J.; Baum, ThomasJournal of Medicinal Chemistry (1989), 32 (7), 1600-6CODEN: JMCMAR; ISSN:0022-2623.The synthesis of spirapril (I, R = Et, R1 = Me) (II), spiraprilat (I, R = H, R1 = Me) (III), their (RSS) stereoisomers, and their glycyl (I, R = Et, R1 = H) and lysyl [I, R = H, Et, R1 = (CH2)4NH2] analogs is described. These compds. were evaluated in vivo for inhibition of angiotensin converting enzyme (ACE), and selected compds. were evaluated for in vitro ACE inhibition (II ID50 16 μg/kg; III IC50 0.8 nM, ID50 8 μg/kg). In anesthetized rats (i.v.), esters II and I [R = Et, R1 = (CH2)4NH2] are more potent than enalapril, and diacids III and I [R = H, R1 = (CH2)4NH2] are more potent than enalaprilat in vitro. In the conscious rats (orally), II and enalapril showed potent and sustained activity at doses of 0.03-1 and 0.1-1 mg/kg, resp. From this work, II was selected for clin. evaluation as an antihypertensive agent.
- 245Noble, S.; Sorkin, E. M. A preliminary review of its pharmacology and therapeutic efficacy in the treatment of hypertension. Drugs 1995, 49, 750– 766, DOI: 10.2165/00003495-199549050-00008[Crossref], [PubMed], [CAS], Google Scholar245https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXlvVKku7w%253D&md5=d04b2856affd31cd79ca054aff60f94aSpirapril. A preliminary review of its pharmacology and therapeutic efficacy in the treatment of hypertensionNoble, Stuart; Sorkin, Eugene M.Drugs (1995), 49 (5), 750-66CODEN: DRUGAY; ISSN:0012-6667.A review with 55 refs. Spirapril is a non-sulfhydryl angiotensin-converting enzyme (ACE) inhibitor prodrug which is converted to the active metabolite spiraprilat following oral administration, and which has been evaluated primarily for the treatment of hypertension. In dose-finding studies of patients with mild to severe hypertension, spirapril ≥6mg once daily produced redns. in blood pressure of approx. 10 to 18mm Hg (systolic) and 7 to 13mm Hg (diastolic) [24-h postdose trough readings at the end of the treatment period]. Blood pressure normalization (trough diastolic blood pressure ≤90mm Hg) had occurred in 29 to 50% of patients at the end of these investigations. Spirapril is generally well tolerated and produces an adverse event profile similar to that of other ACE inhibitors. Further comparative trials are needed to fully det. its efficacy with respect to other ACE inhibitors, and a better understanding of its effects on renal function will clarify its role in hypertensive patients with renal failure.
- 246Sybertz, E. J.; Watkins, R. W.; Ahn, H. S.; Baum, T.; La Rocca, P.; Patrick, J.; Leitz, F. Pharmacologic, metabolic, and toxicologic profile of spirapril (SCH 33844), a new angiotensin converting inhibitor. J. Cardiovasc. Pharmacol. 1987, 10, S105– S108, DOI: 10.1097/00005344-198706107-00020[Crossref], [PubMed], [CAS], Google Scholar246https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1cXktlWkurw%253D&md5=c594ce615397b30f16e4c1b230d4d1f7Pharmacologic, metabolic, and toxicologic profile of spirapril (SCH 33844), a new angiotensin converting inhibitorSybertz, Edmund J.; Watkins, Robert W.; Ahn, Ho Sam; Baum, Thomas; La Rocca, Paul; Patrick, James; Leitz, FrederickJournal of Cardiovascular Pharmacology (1987), 10 (Suppl. 7), S105-S108CODEN: JCPCDT; ISSN:0160-2446.Spirapril (SCH 33844) (I) is a new angiotensin-converting enzyme (ACE) inhibitor. SCH 33844 diacid inhibited hydrolysis of hip-his-leu by rabbit lung ACE in a potent (Ki = 0.74 nM), selective, and noncompetitive fashion. SCH 33844 (0.03-1 mg/kg orally) produced dose-related inhibition of angiotensin I (AI) pressor responses in conscious rats with a duration of 24 h at the higher dose. SCH 33844 (0.3-30 mg/kg orally) reduced blood pressure in a dose-related manner in conscious SHR with a 24-h duration. It appears that peripheral vasodilation is the primary mechanism of the antihypertensive action. The metabolic profile of SCH 33844 was evaluated in dogs and rats. The compd. was absorbed in a dose-proportional manner and excreted primary as the diacid form. In contrast to captopril and enalapril, most of the drug (67%) was excreted into the feces following i.v. dosing. Chronic toxicol. evaluation in dogs and rats demonstrated that the drug was relatively devoid of toxicity at oral doses as high as 400 and 450 mg/kg/day, resp. SCH 33844 is a potent, long acting ACE inhibitor with a low level of toxicity and a metabolic fate that differs from that of enalapril and captopril. Its hemodynamic actions suggest that the compd. should be highly effective in the treatment of hypertension and congestive heart failure.
- 247Guitard, C.; Lohmann, F. W.; Alfiero, R.; Ruina, M.; Alvisi, V. Cardiovasc. Drugs Ther. 1997, 11, 449– 457, DOI: 10.1023/A:1007797405850[Crossref], [PubMed], [CAS], Google Scholar247https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXmt12ltL0%253D&md5=bdfda3b6ee0175ff5ef10637c62ebb5fComparison of efficacy of spirapril and enalapril in control of mild-to-moderate hypertensionGuitard, C.; Lohman, F. W.; Alfiero, R.; Ruina, M.; Alvisi, V.Cardiovascular Drugs and Therapy (1997), 11 (3), 449-457CODEN: CDTHET; ISSN:0920-3206. (Kluwer)The efficacy of spirapril, 6 mg once daily, was compared with enalapril, 5-20 mg once daily, in the control of mild-to-moderate hypertension in a placebo-controlled, parallel-group study. A total of 251 patients participated in the study, all of whom underwent a 4-wk washout period on placebo. Thereafter, 100 patients were randomized to spirapril, 6 mg once daily, 101 patients to enalapril, 5-20 mg once daily, and 50 patients remained on placebo. Sitting diastolic blood pressure (DBP) and systolic blood pressure (SBP) were measured at 2-weekly clinic visits. Blood pressure profiles during peak and trough plasma drug concn. (2-4 h and 24-26 h postdose, resp.) were detd. at baseline and 4 and 8 wk after starting the double-blind phase. Compared with placebo, treatment with both spirapril and enalapril resulted in significant redns. (p<0.001) in DBP and SBP. DBP was reduced to a greater extent with spirapril than with enalapril both at peak (17.4 mmHg vs. -14.8 mmHg) and trough (-14.7 mmHg vs. -12.4 mmHg). Thus, although the trough/peak DBP ratios for spirapril and enalapril were very similar (84% vs. 82%), actual redns. in DBP were different. Spirapril and enalapril treatment resulted in similar redns. in SBP at both peak and through levels. Both drugs were well tolerated, and there were very few adverse events of changes in hematol. or biochem. parameters during the study. In conclusion, spirapril, 6 mg once daily, as the initial and maintenance dose, is at least as effective and well tolerated as enalapril individually titrated.
- 248(a) Yamashita, S.; Matsuzawa, Y. Where are we with probucol: a new life for an old drug?. Atherosclerosis 2009, 207, 16– 23, DOI: 10.1016/j.atherosclerosis.2009.04.002[Crossref], [PubMed], [CAS], Google Scholar.248ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtlyrtbbK&md5=6a5ce431e951d9d3947d34afe909a65eWhere are we with probucol: A new life for an old drug?Yamashita, Shizuya; Matsuzawa, YujiAtherosclerosis (Amsterdam, Netherlands) (2009), 207 (1), 16-23CODEN: ATHSBL; ISSN:0021-9150. (Elsevier B.V.)A review. Probucol has a long history of clin. application with established efficacy and safety profiles. Probucol is a potent anti-oxidant drug that was in clin. use during the past few decades for the treatment and prevention of cardiovascular diseases. Here we review the current status of knowledge on the pharmacol., clin. benefits, and the mechanism of actions of this unique drug. Probucol has diverse pharmacol. properties with therapeutic effects on the cardiovascular systems. Its mechanism of pharmacol. actions at the mol. level has recently been elucidated with the new concept of HDL metab. assocd. with cholesteryl ester transfer protein (CETP) or scavenger receptor class B type I (SR-BI). HDL-C redn. may not be a "side effect" but it most likely might reflect a mechanism of action of probucol. Probucol could be reconsidered as an option at least in case statins, which are known to be effective in lowering low-d. lipoproteins (LDL) and coronary artery disease (CAD) risk, are not effective. In particular, a marked CAD risk redn. was recently reported in long-term probucol treatment of patients with heterozygous familial hypercholesterolemia (FH) in Japan. Therefore, probucol could be a more common therapeutic drug for the treatment of patients with FH as well. There is more than enough reason to believe that this old drug has much more to offer than hitherto known.(b) Buckley, M. M.-T.; Goa, K. L.; Price, A. H.; Brogden, R. N. A reappraisal of its pharmacological properties and therapeutic use in hypercholesterolaemia. Drugs 1989, 37, 761– 800, DOI: 10.2165/00003495-198937060-00002[Crossref], [PubMed], [CAS], Google Scholar248bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1MXkvV2lsLo%253D&md5=8f17d5d08d515cd4b8c11af43c996f61Probucol. A reappraisal of its pharmacological properties and therapeutic use in hypercholesterolemiaBuckley, Micaela M. T.; Goa, Karen L.; Price, Allan H.; Brogden, Rex N.Drugs (1989), 37 (6), 761-800CODEN: DRUGAY; ISSN:0012-6667.A review with ∼150 refs. Probucol appears to be of benefit in primary and secondary hyperlipoproteinemia of Types IIa and IIb, and particularly in homozygous familial hypercholesterolemia, with marked effects on xanthomas, and a generally favorable adverse effect profile. There is no evidence to date causally relating occasional QT interval prolongation in patients to any incidence of arrhythmias or sudden death.
- 249(a) Neuworth, M. B.; Laufer, R. J.; Barnhart, J. W.; Sefranka, J. A.; McIntosh, D. D. Synthesis and hypocholesterolemic activity of alkylidenedithio bisphenols. J. Med. Chem. 1970, 13, 722– 725, DOI: 10.1021/jm00298a031[ACS Full Text.], [CAS], Google Scholar249ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE3cXksVGjtrk%253D&md5=5e6a3e7be76f37d20d5b5a47b7220199Synthesis and hypocholesterolemic activity of alkylidenedithio bisphenolsNeuworth, Martin B.; Laufer, Rohert J.; Barnhart, James W.; Sefranka, J. A.; McIntosh, D. D.Journal of Medicinal Chemistry (1970), 13 (4), 722-5CODEN: JMCMAR; ISSN:0022-2623.The synthesis and serum cholesterol lowering properties of a new class of alkylidenedithio bisphenols and related compds. are discussed. Max. activity is shown by 4,4'-(isopropylidenedithio)bis(2,6-di-tertbutylphenol). A few other members of the class show moderate to good activity and these are produced by substitution of a Me group or an iso-Pr group for one tert-Bu group in the phenolic nucleus, or substitution of Et for Me in the isopropylidene moiety. Other reported structural variations resulted in a redn. of activity or, most often, a loss of activity.(b) Carew, T. E.; Schwenke, D. C.; Steinberg, D. Antiatherogenic effect of probucol unrelated to its hypocholesterolemic effect: Evidence that antioxidants in vivo can selectively inhibit low density lipoprotein degradation in macrophage-rich fatty streaks and slow the progression of atherosclerosis in the Watanabe heritable hyperlipidemic rabbit. Proc. Natl. Acad. Sci. U. S. A. 1987, 84, 7725– 7729, DOI: 10.1073/pnas.84.21.7725[Crossref], [PubMed], [CAS], Google Scholar249bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1cXhs1Whtw%253D%253D&md5=331c3283309fd7686ea664350f0ef961Antiatherogenic effect of probucol unrelated to its hypocholesterolemic effect: evidence that antioxidants in vivo can selectively inhibit low density lipoprotein degradation in macrophage-rich fatty streaks and slow the progression of atherosclerosis in the Watanabe heritable hyperlipidemic rabbitCarew, Thomas E.; Schwenke, Dawn C.; Steinberg, DanielProceedings of the National Academy of Sciences of the United States of America (1987), 84 (21), 7725-9CODEN: PNASA6; ISSN:0027-8424.The studies reported here take advantage of the fact that probucol is an effective antioxidant transported in lipoproteins, including LDL (low-d. lipoprotein) and blocks the oxidative modification of LDL in vitro. Results indicated that the rate of degrdn. of LDL in the macrophage-rich fatty-streak lesions of the LDL receptor-deficient rabbit treated with probucol (1% by wt. in the diet) is reduced to ∼50% of that in the lesions of receptor-deficient rabbits not given probucol (but matched for plasma cholesterol levels). In contrast, the rates of degrdn. in the nonlesioned areas of the aorta were no different in probucol-treated and control animals. Most of the LDL degrdn. in fatty-streak lesions takes place in macrophages, whereas in nonlesioned aorta, which contains very few macrophages, the degrdn. is almost exclusively in endothelial cells and smooth muscle cells. Thus, the results are compatible with the postulate that the native LDL taken up and degraded by foam cells in the developing fatty-streak lesions was in part first converted to a form recognized by the scavenger receptor (by oxidative or analogous modification). Finally, and most importantly, treatment with probucol reduced the rate of development of fatty-streak lesions even though plasma cholesterol levels were no lower than lovastatin-treated (control) rabbits.
- 250Meng, C. Q.; Somers, P. K.; Hoong, L. K.; Zheng, X. S.; Ye, Z.; Worsencroft, K. J.; Simpson, J. E.; Hotema, M. R.; Weingarten, M. D.; MacDonald, M. L.; Hill, R. R.; Marino, E. M.; Suen, K.-L.; Luchoomun, J.; Kunsch, C.; Landers, L. K.; Stefanopoulos, D.; Howard, R. B.; Sundell, C. L.; Saxena, U.; Wasserman, M. A.; Sikorski, J. A. Discovery of novel phenolic antioxidants as inhibitors of vascular cell adhesion molecule-1 expression for use in chronic inflammatory diseases. J. Med. Chem. 2004, 47, 6420– 6432, DOI: 10.1021/jm049685u[ACS Full Text], [CAS], Google Scholar250https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXptVyqsrk%253D&md5=2f498806edd0fa66386d676d9710d404Discovery of Novel Phenolic Antioxidants as Inhibitors of Vascular Cell Adhesion Molecule-1 Expression for Use in Chronic Inflammatory DiseasesMeng, Charles Q.; Somers, Patricia K.; Hoong, Lee K.; Zheng, X. Sharon; Ye, Zhihong; Worsencroft, Kimberly J.; Simpson, Jacob E.; Hotema, Martha R.; Weingarten, M. David; MacDonald, Mathew L.; Hill, Russell R.; Marino, Elaine M.; Suen, Ki-Ling; Luchoomun, Jayraz; Kunsch, Charles; Landers, Laura K.; Stefanopoulos, Dimitria; Howard, Randy B.; Sundell, Cynthia L.; Saxena, Uday; Wasserman, Martin A.; Sikorski, James A.Journal of Medicinal Chemistry (2004), 47 (25), 6420-6432CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Vascular cell adhesion mol.-1 (VCAM-1) mediates recruitment of leukocytes to endothelial cells and is implicated in many inflammatory conditions. Since part of the signal transduction pathway that regulates the activation of VCAM-1 expression is redox-sensitive, compds. with antioxidant properties may have inhibitory effects on VCAM-1 expression. Novel phenolic compds. have been designed and synthesized starting from probucol. Many of these compds. demonstrated potent inhibitory effects on cytokine-induced VCAM-1 expression and displayed potent antioxidant effects in vitro. Some of these derivs. inhibited lipopolysaccharide (LPS)-induced secretion of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 from human peripheral blood mononuclear cells (hPBMCs) in a concn.-dependent manner in vitro and showed antiinflammatory effects in an animal model. Two of the compds. are currently in clin. trials for the treatment of rheumatoid arthritis (RA) and prevention of chronic organ transplant rejection, resp.
- 251(a) Meng, C. Q.; Somers, P. K.; Rachita, C. L.; Holt, L. A.; Hoong, L. K.; Zheng, X. S.; Simpson, J. E.; Hill, R. R.; Olliff, L. K.; Kunsch, C. K.; Sundell, C. L.; Parthasarathy, S.; Saxena, U.; Sikorski, J. A.; Wasserman, M. A. Novel phenolic antioxidants as multifunctional inhibitors of inducible VCAM-1 expression for use in atherosclerosis. Bioorg. Med. Chem. Lett. 2002, 12, 2545– 2548, DOI: 10.1016/S0960-894X(02)00516-4[Crossref], [PubMed], [CAS], Google Scholar.251ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XmsVWju7g%253D&md5=1778dcbd0cd9ff0d621c228f8e647fd2Novel phenolic antioxidants as multifunctional inhibitors of inducible VCAM-1 expression for use in atherosclerosisMeng, Charles Q.; Somers, Patricia K.; Rachita, Carolyn L.; Holt, Lisa A.; Hoong, Lee K.; Zheng, X. Sharon; Simpson, Jacob E.; Hill, Russell R.; Olliff, Lynda K.; Kunsch, Charles; Sundell, Cynthia L.; Parthasarathy, Sampath; Saxena, Uday; Sikorski, James A.; Wasserman, Martin A.Bioorganic & Medicinal Chemistry Letters (2002), 12 (18), 2545-2548CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Science Ltd.)A series of novel phenolic compds. has been discovered as potent inhibitors of TNF-α-inducible expression of vascular cell adhesion mol.-1 (VCAM-1) with concurrent antioxidant and lipid-modulating properties. Optimization of these multifunctional agents led to the identification of AGI-1067 as a clin. candidate with demonstrated efficacies in animal models of atherosclerosis and hyperlipidemia.(b) Muldrew, K. M.; Franks, A. M. Succinobucol: review of the metabolic, antiplatelet and cardiovascular effects. Expert Opin. Invest. Drugs 2009, 18, 531– 539, DOI: 10.1517/13543780902849244[Crossref], [PubMed], [CAS], Google Scholar251bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXjvVWnsb0%253D&md5=dca022c5167225d3343bf55ca18afbeeSuccinobucol: review of the metabolic, antiplatelet and cardiovascular effectsMuldrew, Kendrea M.; Franks, Amy M.Expert Opinion on Investigational Drugs (2009), 18 (4), 531-539CODEN: EOIDER; ISSN:1354-3784. (Informa Healthcare)A review. Background: Succinobucol (AGI-1067) was developed as a probucol deriv. with anti-inflammatory and antioxidant properties. It has undergone Phase III clin. trials to det. its place in the treatment of atherosclerotic disease. Objective: This paper reviews the available history, pharmacol. and preclin. and clin. trial data of succinobucol. Methods: Data were compiled following review of publications indexed in Medline and International Pharmaceutical Abstrs., industry media releases and relevant bibliogs. Results/conclusion: In preclin. studies, succinobucol exhibited antioxidant, anti-inflammatory, antihyperglycemic and antiplatelet properties; however, these effects have not resulted in a redn. in cardiovascular clin. end points in clin. trials. Although proposed antihyperglycemic effects are being investigated, safety concerns and lack of clear cardiovascular benefit may limit its clin. use as an antihyperglycemic agent.
- 252(a) Groso, G.; Caputo, O.; Ceruti, M.; Biglino, G.; Franzone, J. S.; Cirillo, R. Synthesis and antibronchospastic activity of theophylline thioacetal derivatives. Eur. J. Med. Chem. 1989, 24, 635– 638, DOI: 10.1016/0223-5234(89)90035-4 .(b) Franzone, J. S.; Reboani, M. C.; Biglione, V.; Cirillo, R. Pharmacological and toxicological activities of a new methylxanthine derivative [7-(1,3-dithiolan-2-ylmethyl)-1,3-dimethylxanthine] with antibronchospastic and mucoregulatory properties. Drugs Exp. Clin. Res. 1990, 16, 263– 276[PubMed], [CAS], Google Scholar.252bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXhvF2nsL8%253D&md5=4477119dbd86a0553a4e882411193caePharmacological and toxicological activities of a new methylxanthine derivative [7-(1,3-dithiolan-2-ylmethyl)-1,3-dimethylxanthine] with antibronchospastic and mucoregulatory propertiesFranzone, J. S.; Reboani, M. C.; Biglione, V.; Cirillo, R.Drugs under Experimental and Clinical Research (1990), 16 (6), 263-76CODEN: DECRDP; ISSN:0378-6501.7-(1,3-Dithiolan-2-ylmethyl)-1,3-dimethylxanthine (ABC 99) (I) was studied in animals to evaluate its pharmacol. activity. This compd. had markedly greater antibronchospastic activity in vitro and in vivo than aminophylline. It also had moderate antitussive properties and was an active mucoregulator. ABC 99 acted as an intestinal muscle relaxant, but it had no cardiovascular, urinary, or central-nervous side effects. The action of ABC 99 could be explained by its inhibition of guinea pig lung phosphodiesterases and affinity for adenosine receptors, particularly A2 receptors. ABC 99 had low acute toxicity in animals, indicating that it may be useful for treating asthma and chronic bronchitis.(c) Reboani, M. C.; Franzone, J. S. In vivo anti-inflammatory activity of 7-(1,3-dithiolan-2-ylmethyl)-1,3-dimethylxanthine. Drugs Exp. Clin. Res. 1990, 16, 277– 284[PubMed], [CAS], Google Scholar.252chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXhvF2htbc%253D&md5=e891df751e9a28dd13976c4fe732e801In vivo anti-inflammatory activity of 7-(1,3-dithiolan-2-ylmethyl)-1,3-dimethylxanthineReboani, M. C.; Franzone, J. S.Drugs under Experimental and Clinical Research (1990), 16 (6), 277-84CODEN: DECRDP; ISSN:0378-6501.The title methylxanthine deriv. (ABC 99), which has mucoregulatory and antibronchospastic properties, was studied in rats. ABC 99 had marked anti-inflammatory activity in exptl. trials involving the principal mediators of inflammation (platelet-activating factor [PAF], histamine, serotonin, LTC4-like substances, etc.). It inhibited the formation of edemas induced both by carrageenin and PAF in the rat paw, and reduced the increase in vascular permeability induced by histamine and serotonin. ABC 99 also inhibited PAF-induced pleurisy, reducing the vol. of pleural exudate and the presence of LTC4-like substances in the pleural cavity. When administered subacutely, ABC 99 decreased the formation of granulation tissue caused by the s.c. implantation of cotton pellets in the rat. ABC 99 may be of particular interest in the treatment of respiratory disorders involving obstructive inflammation and bronchial hypersensitivity.(d) Cravanzola, C.; Grosa, G.; Franzone, J. S. Kinetic and metabolic studies of 7-(1,3-dithiolan-2-ylmethyl)-1,3-dimethylxanthine in the rat. Drugs Exp. Clin. Res. 1990, 16, 285– 291[PubMed], [CAS], Google Scholar.252dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXitl2rsLo%253D&md5=d6f672fc5cd4d7b3ae472f72f028b3dbKinetic and metabolic studies of 7-(1,3-dithiolan-2-ylmethyl)-1,3-dimethylxanthine in the ratCravanzola, C.; Grosa, G.; Franzone, J. S.Drugs under Experimental and Clinical Research (1990), 16 (6), 285-91CODEN: DECRDP; ISSN:0378-6501.The kinetics (absorption, tissue distribution and excretion) of the title compd. (ABC 99) (I) were studied in the rat. ABC 99 was administered orally at 10, 30 and 100 mg/kg. ABC 99 was rapidly absorbed, metabolized in the liver, and partially excreted in the urine. It was equally distributed in the tissues, including the brain, although in much lower amts. than those absorbed. Three metabolites were identified: theophylline, which was formed in very small quantities, and 2 isomers (cis and trans) of ABC 99 sulfoxide. The latter 2 compds. formed in greater amts. than theophylline, and the trans-isomer predominated. The metabolites were distributed among the tissues, but did not accumulate. Elimination was virtually complete at 24 h. The pharmacol. activity of ABC 99 (antibronchospastic, mucoregulatory and anti-inflammatory) is probably due to the parent compd., which is absorbed unchanged. However, some activity of the 2 sulfoxides cannot be excluded, as they have a structure analogous to that of ABC 99.(e) Grosa, G.; Caputo, O.; Ceruti, M.; Biglino, G.; Franzone, J. S.; Cravanzola, C. Metabolism of 7-(1,3-dithiolan-2-ylmethyl)-1,3-dimethylxanthine by rat liver microsomes. Diastereoselective metabolism of the 1,3-dithiolane ring. Drug Metab. Dispos. 1991, 19, 454– 457[PubMed], [CAS], Google Scholar.252ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXhvF2jsbw%253D&md5=0b366cc6c209e0011b2343581c74491dMetabolism of 7-(1,3-dithiolan-2-ylmethyl)-1,3-dimethylxanthine by rat liver microsomes. Diastereoselective metabolism of the 1,3-dithiolane ringGrosa, Giorgio; Caputo, Otto; Ceruti, Maurizio; Biglino, Giuseppe; Franzone, Jose Sebastian; Cravanzola, CarloDrug Metabolism and Disposition (1991), 19 (2), 454-7CODEN: DMDSAI; ISSN:0090-9556.The metabolic transformation of the antibronchospastic title compd. (ABC-99) was studied in vitro with a rat liver microsomal prepn. contg. an NAPDH-generating system. About 30% ABC-99 was metabolized and the only metabolic pathway obsd. was oxidn. of the 1,3-dithiolane ring. Two distinct sulfoxides were formed diastereoselectively, the trans isomer being the major product in the ratio 7:3. In contrast to the 1,3-dioxolane ring of doxophylline, the 1,3-dithiolane ring of ABC-99 did not undergo oxidative opening through acetal carbon oxidn. No N-dealkylation to theophylline was obsd. This high regioselectivity in vitro was most likely due to the nucleophilicity of the sulfur atom. The diastereoselective sulfoxidn. was apparently catalyzed by flavin-dependent monooxygenases, as no effect was obsd. with CO treatment, whereas selective thermal inactivation reduced the rate of sulfoxidn.(f) Auret, B. J.; Boyd, D. R.; Dunlop, R.; Drake, A. F. Stereoselectivity during fungal sulphoxidations of 1,3-dithiolanes. J. Chem. Soc., Perkin Trans. 1 1988, 2827– 2829, DOI: 10.1039/p19880002827[Crossref], [CAS], Google Scholar252fhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL1cXmt1Knsrw%253D&md5=6136dfd30638e38f89c451ed39b1d236Stereoselectivity during fungal sulfoxidations of 1,3-dithiolanesAuret, Barbara J.; Boyd, Derek R.; Dunlop, Robert; Drake, Alex F.Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999) (1988), (10), 2827-9CODEN: JCPRB4; ISSN:0300-922X.Mono- and disulfoxide products were obtained after addn. of 1,3-dithiolane, 2-methyl-1,3-dithiolane, and 2-t-butyl-1,3-dithiolane as substrates to growing cultures of Aspergillus foetidus, Mortierella isabellina, and a Helminthosporium sp. Enzyme-catalyzed stereodifferentiation between prochiral lone pairs on a S atom gave optically active 1,3-dithiolane 1-oxide (10-65%). The derived optically pure trans-1,3-dithiolane-1,3-dioxide was obtained by fractional recrystn. A stereopreference for the pro-R S atom (61 and 66%) was obsd. during microbial oxidn. of 2-methyl-1,3-dithiolane and 2-t-butyl-1,3-dithiolane, resp. The abs. stereochem. of the dextrorotatory sulfoxide metabolites was assigned the R configuration at the chiral S atoms from CD spectroscopy.
- 253Fulop, F.; Mattinen, J.; Pihlaja, R. Ring-chain tautomerism in 1,2-thiazolidines. Tetrahedron 1990, 46, 6545– 6552, DOI: 10.1016/S0040-4020(01)96019-3[Crossref], [CAS], Google Scholar253https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXmtFemsA%253D%253D&md5=a8aad7f6ce2f771cfb8e6550fd5d5541Ring-chain tautomerism in 1,3-thiazolidinesFulop, Ferenc; Mattinen, Jorma; Pihlaja, KaleviTetrahedron (1990), 46 (18), 6545-52CODEN: TETRAB; ISSN:0040-4020.NMR data show that in general, 1,3-thiazolidines exist as ring tautomers; a detectable amt. of open-chain tautomer was obsd. with (bromohydroxyphenyl)benzothiazoline (eg. I .dblharw. II). The 1,3-thiazolidine ring was ∼104 times more stable that the 1,3-oxazolidine ring.
- 254Singh, G. S. β-lactams in the new millennium. Part-II: Cephems, oxacephems, penams and sulbactam. Mini-Rev. Med. Chem. 2004, 4, 93– 109, DOI: 10.2174/1389557043487547[Crossref], [PubMed], [CAS], Google Scholar254https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhtVagt7o%253D&md5=d250e35611f27756401d720bbcb17fc0β-lactams in the new millennium. Part-II: Cephems, oxacephems, penams and sulbactamSingh, G. S.Mini-Reviews in Medicinal Chemistry (2004), 4 (1), 93-109CODEN: MMCIAE; ISSN:1389-5575. (Bentham Science Publishers Ltd.)A review. β-Lactam ring-contg. compds. such as penicillins, ampicillin, amoxicillin, cephalosporins and carbapenems are among the most famous antibiotics. This article reviews the recent developments in study of cephems, oxacephems, penams and sulbactam. Many of the compds. reviewed have potential antibacterial activity, even against resistant strains such as MRSA, and enzyme inhibitory activity.
- 255Bush, K.; Bradford, P. A. β-Lactams and β-lactamase inhibitors: an overview. Cold Spring Harbor Perspect. Med. 2016, 6, a025247 DOI: 10.1101/cshperspect.a025247[Crossref], [PubMed], [CAS], Google Scholar255https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXns1ygs7o%253D&md5=b66594b35c40b109cdab439c3664aba9β-Lactams and β-lactamase inhibitors: an overviewBush, Karen; Bradford, Patricia A.Cold Spring Harbor Perspectives in Medicine (2016), 6 (8), a025247/1-a025247/23CODEN: CSHPFV; ISSN:2157-1422. (Cold Spring Harbor Laboratory Press)β-Lactams are the most widely used class of antibiotics. Since the discovery of benzylpenicillin in the 1920s, thousands of new penicillin derivs. and related β-lactam classes of cephalosporins, cephamycins, monobactams, and carbapenems have been discovered. Each new class of β-lactam has been developed either to increase the spectrum of activity to include addnl. bacterial species or to address specific resistance mechanisms that have arisen in the targeted bacterial population. Resistance to β-lactams is primarily because of bacterially produced β-lactamase enzymes that hydrolyze the β-lactam ring, thereby inactivating the drug. The newest effort to circumvent resistance is the development of novel broad-spectrum β-lactamase inhibitors that work against many problematic β-lactamases, including cephalosporinases and serine-based carbapenemases, which severely limit therapeutic options. This work provides a comprehensive overview of β-lactam antibiotics that are currently in use, as well as a look ahead to several new compds. that are in the development pipeline.
- 256Szultka, M.; Krzeminski, R.; Jackowski, M.; Buszewski, B. Identification of in vitro metabolites of amoxicillin in human liver microsomes by LC-ESI/MS. Chromatographia 2014, 77, 1027– 1035, DOI: 10.1007/s10337-014-2648-2[Crossref], [PubMed], [CAS], Google Scholar256https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXkslemsbo%253D&md5=e61d287ca77a82a5ca43324bac40e73cIdentification of In Vitro Metabolites of Amoxicillin in Human Liver Microsomes by LC-ESI/MSSzultka, Malgorzata; Krzeminski, Rafal; Jackowski, Marek; Buszewski, BoguslawChromatographia (2014), 77 (15-16), 1027-1035CODEN: CHRGB7; ISSN:0009-5893. (Springer)Amoxicillin (AMOX) metab. in human liver microsomes was studied in vitro using liq. chromatog.-mass spectrometry (LC/MS). Amoxicillin was incubated with human liver microsomes along with NADPH, and the reaction mixt. was analyzed by LC/MS to obtain the specific metabolic profile of the studied antibiotic drug. Pos. electrospray ionization was employed as the ionization source. An ACE C18-column (4.6 mm × 150 mm, 3 μm) was implemented with acetonitrile and water (+0.1 % formic acid) in isocratic mode as the mobile phase at the flow 0.4 mL min-1. The chem. structures of metabolites were proposed on the basis of the accurate mass measurement of the protonated mol. as well as their main product. Six phase I and one phase II metabolites were detected and structurally described. The metab. of AMOX occurred via oxidn., hydroxylation and oxidative deamination, as well as through combination of these reactions. Compd. M7, with glucuronic acid was also obsd. as phase II metabolite. Neither sulfate nor glutathione conjugates were detected. This study presents novel information about the chem. structure of the potential AMOX metabolites and provides vital data for further pharmacokinetic and in vivo metab. studies.
- 257Smith, P. W.; Zuccotto, F.; Bates, R. H.; Martinez-Martinez, M. S.; Read, K. D.; Peet, C.; Epemolu, O. Pharmacokinetics of β-lactam antibiotics: clues from the past to help discover long-acting oral drugs in the future. ACS Infect. Dis. 2018, 4, 1439– 1447, DOI: 10.1021/acsinfecdis.8b00160[ACS Full Text], [CAS], Google Scholar257https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsFOrtbfF&md5=ca8591280316b2c1733e911feb5f0150Pharmacokinetics of β-Lactam Antibiotics: Clues from the Past To Help Discover Long-Acting Oral Drugs in the FutureSmith, Paul W.; Zuccotto, Fabio; Bates, Robert H.; Martinez-Martinez, Maria Santos; Read, Kevin D.; Peet, Caroline; Epemolu, OlaACS Infectious Diseases (2018), 4 (10), 1439-1447CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)A review. β-Lactams represent perhaps the most important class of antibiotics yet discovered. However, despite many years of active research, none of the currently approved drugs in this class combine oral activity with long duration of action. Recent developments suggest that new β-lactam antibiotics with such a profile would have utility in the treatment of tuberculosis. Consequently, the historical β-lactam pharmacokinetic data have been compiled and analyzed to identify possible directions and drug discovery strategies aimed toward new β-lactam antibiotics with this profile.
- 258(a) Drawz, S. M.; Bonomo, R. A. Three decades of β-lactamase inhibitors. Clin. Microbiol. Rev. 2010, 23, 160– 201, DOI: 10.1128/CMR.00037-09[Crossref], [PubMed], [CAS], Google Scholar.258ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXks1Sktbs%253D&md5=27cd9fca0d848185d9c61e5a25d2c601Three decades of β-lactamase inhibitorsDrawz, Sarah M.; Bonomo, Robert A.Clinical Microbiology Reviews (2010), 23 (1), 160-201CODEN: CMIREX; ISSN:0893-8512. (American Society for Microbiology)A review. Since the introduction of penicillin, β-lactam antibiotics have been the antimicrobial agents of choice. Unfortunately, the efficacy of these life-saving antibiotics is significantly threatened by bacterial β-lactamases. β-Lactamases are now responsible for resistance to penicillins, extended-spectrum cephalosporins, monobactams, and carbapenems. In order to overcome β-lactamase-mediated resistance, β-lactamase inhibitors (clavulanate, sulbactam, and tazobactam) were introduced into clin. practice. These inhibitors greatly enhance the efficacy of their partner β-lactams (amoxicillin, ampicillin, piperacillin, and ticarcillin) in the treatment of serious Enterobacteriaceae and penicillin-resistant staphylococcal infections. However, selective pressure from excess antibiotic use accelerated the emergence of resistance to β-lactam-β-lactamase inhibitor combinations. Furthermore, the prevalence of clin. relevant β-lactamases from other classes that are resistant to inhibition is rapidly increasing. There is an urgent need for effective inhibitors that can restore the activity of β-lactams. Here, we review the catalytic mechanisms of each β-lactamase class. We then discuss approaches for circumventing β-lactamase-mediated resistance, including properties and characteristics of mechanism-based inactivators. We next highlight the mechanisms of action and salient clin. and microbiol. features of β-lactamase inhibitors. We also emphasize their therapeutic applications. We close by focusing on novel compds. and the chem. features of these agents that may contribute to a "second generation" of inhibitors. The goal for the next 3 decades will be to design inhibitors that will be effective for more than a single class of β-lactamases.(b) Gonzalez-Bello, C.; Rodríguez, D.; Pernas, M.; Rodríguez, A.; Colchon, E. β-Lactamase inhibitors to restore the efficacy of antibiotics against superbugs. J. Med. Chem. 2020, 63, 1859– 1881, DOI: 10.1021/acs.jmedchem.9b01279[ACS Full Text], [CAS], Google Scholar258bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitVOhsb3J&md5=336d7eb65305b05d909584c6ae3af6a8β-Lactamase Inhibitors To Restore the Efficacy of Antibiotics against SuperbugsGonzalez-Bello, Concepcion; Rodriguez, Diana; Pernas, Marina; Rodriguez, Angela; Colchon, EstherJournal of Medicinal Chemistry (2020), 63 (5), 1859-1881CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. Infections caused by resistant bacteria are nowadays too common and some pathogens have even become resistant to multiple types of antibiotics, in which cases few or even no treatments are available. In recent years, the most successful strategy in anti-infective drug discovery for the treatment of such problematic infections is the combination therapy 'antibiotic + inhibitor of resistance'. These inhibitors allow the repurposing of antibiotics that have already proven to be safe and effective for clin. use. Three main types of compds. have been developed to block the principal bacterial resistance mechanisms: (i) β-lactamase inhibitors; (ii) outer membrane permeabilizers; and (iii) efflux pump inhibitors. This perspective article is focused on β-lactamase inhibitors that disable the most prevalent cause of antibiotic resistance in Gram-neg. bacteria, i.e., the deactivation of the most widely used antibiotics, β-lactams (penicillins, cephalosporines, carbapenems and monobactams), by the prodn. of β-lactamases. An overview of the most recently identified β-lactamase inhibitors and of combination therapy is provided. The article also covers the mechanism of action of the different types of β-lactamase enzymes as a basis for inhibitor design and target inactivation.
- 259English, A. R.; Retsema, J. A.; Girard, A. E.; Lynch, J. E.; Barth, W. E. CP-45,899, a beta-lactamase inhibitor that extends the antibacterial spectrum of beta-lactams: initial bacteriological characterization. Antimicrob. Agents Chemother. 1978, 14, 414– 419, DOI: 10.1128/AAC.14.3.414[Crossref], [PubMed], [CAS], Google Scholar259https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE1MXhtVSm&md5=abcc968e2de6ec25ca4520aebaf9e4c6CP-45,899, a beta-lactamase inhibitor that extends the antibacterial spectrum of beta-lactams: initial bacteriological characterizationEnglish, Arthur R.; Retsema, James A.; Girard, Arthur E.; Lynch, John E.; Barth, Wayne E.Antimicrobial Agents and Chemotherapy (1978), 14 (3), 414-19CODEN: AMACCQ; ISSN:0066-4804.In the presence of low concns. of CP 45,899 (I) [68373-14-8], a β-lactamase [9073-60-3] inhibitor, ampicillin [69-53-4] and other β-lactams readily inhibited the growth of a variety of resistant bacteria that contain β-lactamases. I used alone displayed only weak antibacterial activity, with the notable exception of its potent effects on susceptible and resistant strains of Neisseria gonorrhoeae. I appeared to be somewhat less potent but markedly more stable (in aq. soln.) than the recently described β-lactamase inhibitor clavulanic acid [58001-44-8]. The spectrum extensions provided by the 2 compds. were similar. A 1:1 mixt. of I and ampicillin displayed marked antimicrobial activity in mice exptl. infected with ampicillin-resistant Staphylococcus aureus, Haemophilus influenzae, Klebsiella pneumoniae, and Proteus vulgaris.
- 260English, A. R.; Retsema, J. A.; Girard, A. E.; Lynch, J. E.; Barth, W. E. CP-45,899, a β-lactamase inhibitor that extends the antibacterial spectrum of β-lactams: initial bacteriological characterization. Antimicrob. Agents Chemother. 1978, 14, 414– 419, DOI: 10.1128/AAC.14.3.414[Crossref], [PubMed], [CAS], Google Scholar260https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE1MXhtVSm&md5=abcc968e2de6ec25ca4520aebaf9e4c6CP-45,899, a beta-lactamase inhibitor that extends the antibacterial spectrum of beta-lactams: initial bacteriological characterizationEnglish, Arthur R.; Retsema, James A.; Girard, Arthur E.; Lynch, John E.; Barth, Wayne E.Antimicrobial Agents and Chemotherapy (1978), 14 (3), 414-19CODEN: AMACCQ; ISSN:0066-4804.In the presence of low concns. of CP 45,899 (I) [68373-14-8], a β-lactamase [9073-60-3] inhibitor, ampicillin [69-53-4] and other β-lactams readily inhibited the growth of a variety of resistant bacteria that contain β-lactamases. I used alone displayed only weak antibacterial activity, with the notable exception of its potent effects on susceptible and resistant strains of Neisseria gonorrhoeae. I appeared to be somewhat less potent but markedly more stable (in aq. soln.) than the recently described β-lactamase inhibitor clavulanic acid [58001-44-8]. The spectrum extensions provided by the 2 compds. were similar. A 1:1 mixt. of I and ampicillin displayed marked antimicrobial activity in mice exptl. infected with ampicillin-resistant Staphylococcus aureus, Haemophilus influenzae, Klebsiella pneumoniae, and Proteus vulgaris.
- 261Papp-Wallace, K. M.; Bethel, C. R.; Caillon, J.; Barnes, M. D.; Potel, G.; Bajaksouzian, S.; Rutter, J. D.; Reghal, A.; Shapiro, S.; Taracila, M. A.; Jacobs, M. R.; Bonomo, R. A.; Jacqueline, C. Beyond piperacillin-tazobactam: cefepime and AAI101 as a potent β-lactam-β-lactamase inhibitor combination. Antimicrob. Agents Chemother. 2019, 63, e00105 DOI: 10.1128/AAC.00105-19[Crossref], [PubMed], [CAS], Google Scholar261https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtFeiur%252FE&md5=55a99d1c91a4f138479ad35e507f1c99Beyond piperacillin-tazobactam: cefepime and AAI101 as a potent β-Lactam-β-lactamase inhibitor combinationPapp-Wallace, Krisztina M.; Bethel, Christopher R.; Caillon, Jocelyne; Barnes, Melissa D.; Potel, Gilles; Bajaksouzian, Saralee; Rutter, Joseph D.; Reghal, Amokrane; Shapiro, Stuart; Taracila, Magdalena A.; Jacobs, Michael R.; Bonomo, Robert A.; Jacqueline, CedricAntimicrobial Agents and Chemotherapy (2019), 63 (5), e00105-19/1-e00105-19/17CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)Impeding, as well as reducing, the burden of antimicrobial resistance in Gram-neg. pathogens is an urgent public health endeavor. Our current antibiotic armamentarium is dwindling, while major resistance determinants (e.g., extendedspectrum β-lactamases [ESBLs]) continue to evolve and disseminate around the world. One approach to attack this problem is to develop novel therapies that will protect our current agents. AAI101 is a novel penicillanic acid sulfone β-lactamase inhibitor similar in structure to tazobactam, with one important difference. AAI101 possesses a strategically placed Me group that gives the inhibitor a net neutral charge, enhancing bacterial cell penetration. AAI101 paired with cefepime, also a zwitterion, is in phase III of clin. development for the treatment of serious Gram-neg. infections. Here, AAI101 was found to restore the activity of cefepime against class A ESBLs (e.g., CTX-M-15) and demonstrated increased potency compared to that of piperacillin-tazobactam when tested against an established isogenic panel. The enzymol. properties of AAI101 further revealed that AAI101 possessed a unique mechanism of β-lactamase inhibition compared to that of tazobactam. Addnl., upon reaction with AAI101, CTX-M-15 was modified to an inactive state. Notably, the in vivo efficacy of cefepime-AAI101 was demonstrated using a mouse septicemia model, indicating the ability of AAI101 to bolster significantly the therapeutic efficacy of cefepime in vivo. The combination of AAI101 with cefepime represents a potential carbapenem-sparing treatment regimen for infections suspected to be caused by Enterobacteriaceae expressing ESBLs.
- 262Chen, Y. L.; Chang, C. W.; Hedberg, K. Synthesis of a potent β-lactamase inhibitor-1,1-dioxo-6-(2-pyridyl)methylenepenicillanic acid and its reaction with sodium methoxide. Tetrahedron Lett. 1986, 27, 3449– 3452, DOI: 10.1016/S0040-4039(00)84819-4[Crossref], [CAS], Google Scholar262https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL2sXktVKqtb4%253D&md5=1b214250114c91fad210d2c8d2f61909Synthesis of a potent β-lactamase inhibitor - 1,1-dioxo-6-(2-pyridyl)methylenepenicillanic acid and its reaction with sodium methoxideChen, Yuhpyng L.; Chang, Chi Wu; Hedberg, KirkTetrahedron Letters (1986), 27 (30), 3449-52CODEN: TELEAY; ISSN:0040-4039.1,1-Dioxo-6-(2-pyridyl)methylenepenicillanic acid (I) was preped. in 4 steps from ester II by oxidn., Wittig reaction with 2-picolyltriphenylphosphonium chloride, oxidn. by m-chloroperoxybenzoic acid, and deallylation, and found to be a potent β-lactamase inhibitor. Its reaction with NaOMe was studied to provide insight into its mechanism of enzyme inactivation.
- 263(a) Vazquez-Ucha, J. C.; Maneiro, M.; Martinez-Guitian, M.; Buynak, J.; Bethel, C. R.; Bonomo, R. A.; Bou, G.; Poza, M.; Gonzalez-Bello, C.; Beceiro, A. Activity of the β-lactamase inhibitor LN-1–255 against carbapenem-hydrolyzing class D β-lactamases from Acinetobacter baumannii. Antimicrob. Agents Chemother. 2017, 61, e01172–17 DOI: 10.1128/AAC.01172-17 .(b) Vázquez-Ucha, J. C.; Martínez-Guitián, M.; Maneiro, M.; Conde-Perez, K.; Álvarez-Fraga, L.; Torrens, G.; Oliver, A.; Buynak, J. D.; Bonomo, R. A.; Bou, G.; González-Bello, C.; Poza, M.; Beceiro, A. Therapeutic efficacy of LN-1–255 in combination with imipenem in severe infection caused by carbapenem-resistant Acinetobacter baumannii. Antimicrob. Agents Chemother. 2019, 63, e01092 DOI: 10.1128/AAC.01092-19[Crossref], [PubMed], [CAS], Google Scholar263bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXit1eisbrJ&md5=c53b4095cd6a9de4639d125e2e07b333Therapeutic efficacy of LN-1-255 in combination with imipenem in severe infection caused by carbapenem-resistant Acinetobacter baumanniiVazquez-Ucha, Juan Carlos; Martinez-Guitian, Marta; Maneiro, Maria; Conde-Perez, Kelly; Alvarez-raga, Laura; Torrens, Gabriel; Oliver, Antonio; Buynak, John D.; Bonomo, Robert A.; Bou, German; Gonzalez-Bello, Concepcion; Poza, Margarita; Beceiroa, AlejandroAntimicrobial Agents and Chemotherapy (2019), 63 (10), e01092-19CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)The carbapenem-hydrolyzing class D β-lactamases (CHDLs) are the main mechanism of carbapenem resistance in Acinetobacter baumannii. CHDLs are not effectively inactivated by clin. available β-lactam-type inhibitors. We have previously described the in vitro efficacy of the inhibitor LN-1-255 in combination with carbapenems. The aim of this study was to compare the efficacy of LN-1-255 with that of imipenem in murine pneumonia using A. baumannii strains carrying their most extended carbapenemases, OXA-23 and OXA-24/40. The blaOXA-23 and blaOXA-24/40 genes were cloned into the carbapenem-susceptible A. baumannii ATCC 17978 strain. Clin. isolates Ab1 and JC12/04, producing the enzymes OXA-23 and OXA-24/40, resp., were used in the study. Pharmacokinetic (PK) parameters were detd. An exptl. pneumonia model was used to evaluate the efficacy of the combined imipenem-LN-1-255 therapy. MICs of imipenem decreased between 32- and 128-fold in the presence of LN-1-255. I.m. treatment with imipenem-LN-1-255 (30/50 mg/kg) decreased the bacterial burden by (i) 4 and 1.7 log10 CFU/g lung in the infection with the ATCC 17978-OXA-23 and Ab1 strains, resp., and by (ii) 2.5 and 4.5 log10 CFU/g lung in the infection produced by the ATCC 17978-OXA-24/40 and the JC12/04 strains, resp. In all assays, combined therapy offered higher protection against pneumonia than that provided by monotherapy. No toxicity was obsd. in treated mice. Imipenem treatment combined with LN-1-255 treatment significantly reduced the severity of infection by carbapenem-resistant A. baumannii strains carrying CHDLs. Preclin. assays demonstrated the potential of LN-1-255 and imipenem therapy as a new antibacterial treatment.
- 264Lee, M.-H. H.; Graham, G. G.; Williams, K. M.; Day, R. O. A benefit-risk assessment of benzbromarone in the treatment of gout: was its withdrawal from the market in the best interest of patients?. Drug Saf. 2008, 31, 643– 665, DOI: 10.2165/00002018-200831080-00002[Crossref], [PubMed], [CAS], Google Scholar264https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXht1CmtbzO&md5=2f06e6058b5d2b0dddaad2285bae5053A benefit-risk assessment of benzbromarone in the treatment of gout: was its withdrawal from the market in the best interest of patients?Lee, Ming-Han H.; Graham, Garry G.; Williams, Kenneth M.; Day, Richard O.Drug Safety (2008), 31 (8), 643-665CODEN: DRSAEA; ISSN:0114-5916. (Wolters Kluwer Health)A review. Benzbromarone, a potent uricosuric drug, was introduced in the 1970s and was viewed as having few assocd. serious adverse reactions. It was registered in about 20 countries throughout Asia, South America and Europe. In 2003, the drug was withdrawn by Sanofi-Synthelabo, after reports of serious hepatotoxicity, although it is still marketed in several countries by other drug companies. The withdrawal has greatly limited its availability around the world, and increased difficulty in accessing it in other countries where it has never been available. The overall aim of this paper is to det. if the withdrawal of benzbromarone was in the best interests of gouty patients and to present a benefit-risk assessment of benzbromarone. To det. this, we examd. (i) the clin. benefits assocd. with benzbromarone treatment and compared them with the success of alternative therapies such as allopurinol and probenecid, particularly in patients with renal impairment; (ii) the attribution of the reported cases of hepatotoxicity to treatment with benzbromarone; (iii) the incidence of hepatotoxicity possibly due to benzbromarone; (iv) adverse reactions to allopurinol and probenecid. From these analyses, we present recommendations on the use of benzbromarone. Large redns. in plasma urate concns. in patients with hyperuricemia are achieved with benzbromarone and most patients normalize their plasma urate. The half-life of benzbromarone is generally short (about 3 h); however, a uricosuric metabolite, 6-hydroxybenzbromarone, has a much longer half-life (up to 30 h) and is the major species responsible for the uricosuric activity of benzbromarone, although its metab. by cytochrome P 450 (CYP) 2C9 in the liver may vary between patients as a result of polymorphisms in this enzyme. It is effective in patients with moderate renal impairment. Std. dosages of benzbromarone (100 mg/day) tend to produce greater hypouricemic effects than std. doses of allopourinol (300 mg/day) or probenecid (1000 mg/day). Adverse effects assocd. with benzbromarone are relatively infrequent, but potentially severe. Four cases of benzbromarone-induced hepatotoxicity were identified from the literature. Eleven cases have been reported by Sanofi-Synthelabo, but details are not available in the public domain. Only one of the four published cases demonstrated a clear relationship between the drug and liver injury as demonstrated by rechallenge. The other three cases lacked incontrovertible evidence to support a diagnosis of benzbromarone-induced hepatotoxicity. If all the reported cases are assumed to be due to benzbromarone, the estd. risk of hepatotoxicity in Europe was approx. 1 in 17 000 patients but may be higher in Japan. Benzbromarone is also an inhibitor of CYP2C9 and so may be involved in drug interactions with drugs dependent on this enzyme for clearance, such as warfarin. Alternative drugs to benzbromarone have significant adverse reactions. Allopurinol is assocd. with rare life-threatening hypersensitivity syndromes; the risk of these reactions is approx. 1 in 56 000. Rash occurs in approx. 2% of patients taking allopurinol and usually leads to cessation of prescription of the drug. Probenecid has also been assocd. with life-threatening reactions in a very small no. of case reports, but it frequently interacts with many renally excreted drugs. Febuxostat is a new xanthine oxidoreductase inhibitor, which is still in clin. trials, but abnormal liver function is the most commonly reported adverse reaction. Even assuming a causal relationship between benzbromarone and hepatotoxicity in the identified cases, benefit-risk assessment based on total exposure to the drug does not support the decision by the drug company to withdraw benzbromarone from the market given the paucity of alternative options. It is likely that the risks of hepatotoxicity could be ameliorated by employing a graded dosage increase, together with regular monitoring of liver function. Detn. of CYP2C9 status and consideration of potential interactions through inhibition of this enzyme should be considered. The case for wider and easier availability of benzbromarone for treating selected cases of gout is compelling, particularly for patients in whom allopurinol produces insufficient response or toxicity. We conclude that the withdrawal of benzbromarone was not in the best interest of patients with gout.
- 265(a) Uda, J.; Kobashi, S.; Miyata, S.; Ashizawa, N.; Matsumoto, K.; Iwanaga, T. Discovery of dotinurad (FYU-981), a new phenol derivative with highly potent uric acid lowering activity. ACS Med. Chem. Lett. 2020, 11, 2017– 2023, DOI: 10.1021/acsmedchemlett.0c00176[ACS Full Text.], [CAS], Google Scholar265ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtl2rsrzI&md5=d9b7f1b3d44de3d66b2dfff439360b4cDiscovery of Dotinurad (FYU-981), a New Phenol Derivative with Highly Potent Uric Acid Lowering ActivityUda, Junichiro; Kobashi, Seiichi; Miyata, Sachiho; Ashizawa, Naoki; Matsumoto, Koji; Iwanaga, TakashiACS Medicinal Chemistry Letters (2020), 11 (10), 2017-2023CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)To derive new uricosuric agents, novel phenol derivs. were synthesized to overcome the disadvantages of benzbromarone (BBR), attributed by its structural features. Herein, we report the discovery of new phenol derivs. with a 1,1-dioxo-1,2-dihydro-3H-1,3-benzothiazole scaffold. The selected compd. 11 (dotinurad, 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-1,2-dihydro-3H-1,3-benzothiazole, FYU-981, [1285572-51-1]) demonstrated remarkable inhibitory activity on uric acid uptake by primary human renal proximal tubule epithelial cells (RPTECs) and URAT1-mediated uric acid transport, with weak inhibitory activity against mitochondrial respiration. Dotinurad also displayed favorable pharmacokinetic profiles and higher potency in decreasing uric acid than BBR did in Cebus monkeys. Dotinurad has been approved as a new uricosuric medicine in Japan. Our strategy, which focuses on the structural features resulting in unfavorable effects, could be applied to the future developments of other drugs with disadvantages, particularly those having a bis-aryl ketone structure.(b) Omura, K.; Miyata, K.; Kobashi, S.; Ito, A.; Fushimi, M.; Uda, J.; Sasaki, T.; Iwanaga, T.; Ohashi, T. Ideal pharmacokinetic profile of dotinurad as a selective reabsorption inhibitor. Drug Metab. Pharmacokinet. 2020, 35, 313– 320, DOI: 10.1016/j.dmpk.2020.03.002[Crossref], [PubMed], [CAS], Google Scholar265bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXkvFagsb4%253D&md5=e2c708f51a52f2c2c49259f5c5e58e01Ideal pharmacokinetic profile of dotinurad as a selective urate reabsorption inhibitorOmura, Koichi; Miyata, Kengo; Kobashi, Seiichi; Ito, Azusa; Fushimi, Masahiko; Uda, Junichiro; Sasaki, Tomomitsu; Iwanaga, Takashi; Ohashi, TetsuoDrug Metabolism and Pharmacokinetics (2020), 35 (3), 313-320CODEN: DMPRB8; ISSN:1347-4367. (Elsevier B.V.)Dotinurad, a novel selective urate reabsorption inhibitor (SURI), has potent inhibitory effects at low doses on the uptake of urate by urate transporter 1 (URAT1, solute carrier family 22 member 12 [SLC22A12]), localized at the apical membrane of renal proximal tubular cells. This study sought to clarify the pharmacokinetic (PK) profile of dotinurad. In rats, monkeys, and humans, the apparent distribution vol. (0.257, 0.205, and 0.182 L/kg, resp.) and oral clearance (0.054, 0.037, and 0.013 L·h-1·kg-1, resp.) of dotinurad were very low, whereas plasma and luminal concns. were adequately maintained at high levels. In addn., species differences were scarcely obsd. with plasma protein binding of 99.4%. The main metabolite was dotinurad glucuronide (no specific metabolites in humans), and percentage excretion of unchanged dotinurad was low in all the investigated species. The risk of drug interaction with dotinurad was expected to be low, because it weakly inhibits metabolic enzymes such as cytochrome P 450 (CYP). In conclusion, low-dose dotinurad exhibited excellent pharmacol. effects as well as ideal PK properties as a SURI.
- 266Hansen, A. H.; Sergeev, E.; Bolognini, D.; Sprenger, R. R.; Ekberg, J. H.; Ejsing, C. S.; McKenzie, C. J.; Ulven, E. R.; Milligan, G.; Ulven, T. Discovery of a potent thiazolidine free fatty acid receptor 2 agonist with favorable pharmacokinetic properties. J. Med. Chem. 2018, 61, 9534– 9550, DOI: 10.1021/acs.jmedchem.8b00855[ACS Full Text], [CAS], Google Scholar266https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhslKqtrbO&md5=932b2b9e1a00988ee067bb34b2d871acDiscovery of a Potent Thiazolidine Free Fatty Acid Receptor 2 Agonist with Favorable Pharmacokinetic PropertiesHansen, Anders Hoejgaard; Sergeev, Eugenia; Bolognini, Daniele; Sprenger, Richard R.; Ekberg, Jeppe Hvidtfeldt; Ejsing, Christer S.; McKenzie, Christine J.; Rexen Ulven, Elisabeth; Milligan, Graeme; Ulven, TrondJournal of Medicinal Chemistry (2018), 61 (21), 9534-9550CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Free fatty acid receptor 2 (FFA2/GPR43) is a receptor for short-chain fatty acids reported to be involved in regulation of metab., appetite, fat accumulation, and inflammatory responses and is a potential target for treatment of various inflammatory and metabolic diseases. By bioisosteric replacement of the central pyrrolidine core of a previously disclosed FFA2 agonist with a synthetically more tractable thiazolidine, authors were able to rapidly synthesize and screen analogs modified at both the 2- and 3-positions on the thiazolidine core. Herein, they report SAR exploration of thiazolidine FFA2 agonists and the identification of (2R,4R)-2-(2-chlorophenyl)-3-(4-(3,5-dimethylisoxazol-4-yl)benzoyl)thiazolidine-4-carboxylic acid (31, TUG-1375), a compd. with significantly increased potency (7-fold in a cAMP assay) and reduced lipophilicity (50-fold reduced clogP) relative to the pyrrolidine lead structure. The compd. has high soly., high chem., microsomal, and hepatocyte stability, and favorable pharmacokinetic properties and was confirmed to induce human neutrophil mobilization and to inhibit lipolysis in murine adipocytes.
- 267(a) Edmondson, S. D.; Mastracchio, A.; Beconi, M.; Colwell, L. F.; Habulihaz, B.; He, H.; Kumar, S.; Leiting, B.; Lyons, K. A.; Mao, A.; Marsilio, F.; Patel, R. A.; Wu, J. K.; Zhu, L.; Thornberry, N.; Weber, A.; Parmee, E. R. Potent and selective proline derived dipeptidyl peptidase IV inhibitors. Bioorg. Med. Chem. Lett. 2004, 14, 5151– 5155, DOI: 10.1016/j.bmcl.2004.07.056[Crossref], [PubMed], [CAS], Google Scholar.267ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXns1Ohu7o%253D&md5=a60ab88a8e75d41cb7eee30b4c950005Potent and selective proline derived dipeptidyl peptidase IV inhibitorsEdmondson, Scott D.; Mastracchio, Anthony; Beconi, Maria; Colwell, Lawrence F.; Habulihaz, Bahanu; He, Huaibing; Kumar, Sanjeev; Leiting, Barbara; Lyons, Kathryn A.; Mao, Ann; Marsilio, Frank; Patel, Reshma A.; Wu, Joseph K.; Zhu, Lan; Thornberry, Nancy A.; Weber, Ann E.; Parmee, Emma R.Bioorganic & Medicinal Chemistry Letters (2004), 14 (20), 5151-5155CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Inhouse screening of the Merck sample collection identified proline derived homophenylalanine I as a DPP-IV inhibitor with modest potency (DPP-IV IC50 = 1.9 μM). Optimization of I led to a compd. which is among the most potent and selective DPP-IV inhibitors discovered to date.(b) Park, W. S.; Kang, S. K.; Jun, M. A.; Shin, M. S.; Kim, K. Y.; Rhee, S. D.; Bae, M. A.; Kim, M. S.; Kim, K. R.; Kang, N. S.; Yoo, S.; Lee, J. O.; Song, D. Y.; Silinski, P.; Schneider, S. E.; Ahn, J. H.; Kim, S. S. Discovery of β-aminoacyl containing thiazolidine derivatives as potent and selective dipeptidyl peptidase IV inhibitors. Bioorg. Med. Chem. Lett. 2011, 21, 1366– 1370, DOI: 10.1016/j.bmcl.2011.01.041[Crossref], [PubMed], [CAS], Google Scholar267bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXit1GmtLk%253D&md5=df0884cce72f1340b9610310682c2735Discovery of β-aminoacyl containing thiazolidine derivatives as potent and selective dipeptidyl peptidase IV inhibitorsPark, Woul Seong; Kang, Seung Kyu; Jun, Mi Ae; Shin, Mi Sik; Kim, Ki Young; Rhee, Sang Dal; Bae, Myung Ae; Kim, Min Sun; Kim, Kwang Rok; Kang, Nam Sook; Yoo, Sung-eun; Lee, Jie Oh; Song, Dong Hyun; Silinski, Peter; Schneider, Stephen Edward; Ahn, Jin Hee; Kim, Sung SooBioorganic & Medicinal Chemistry Letters (2011), 21 (5), 1366-1370CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A series of β-aminoacyl contg. thiazolidine derivs. was synthesized and evaluated for their ability to inhibit DPP-IV. Several thiazolidine derivs. with an acid moiety were found to be potent DPP-IV inhibitors. Among them, I is the most active in this series with an IC50 value of 1 nM, and it showed excellent selectivity over DPP-IV related enzymes including DPP-2, DPP-8, and DPP-9. I is chem. and metabolically stable, and showed no CYP inhibition, hERG binding or cytotoxicity. The Et ester prodrug of I showed good in vivo DPP-IV inhibition after oral administration in rat and dog models.
- 268Carzaniga, L.; Amari, G.; Rizzi, A.; Capaldi, C.; Fanti, R. D.; Ghidini, E.; Villetti, G.; Carnini, C.; Moretto, N.; Facchinetti, F.; Caruso, P.; Marchini, G.; Battipaglia, L.; Patacchini, R.; Cenacchi, V.; Volta, R.; Amadei, F.; Pappani, A.; Capacchi, S.; Bagnacani, V.; Delcanale, M.; Puccini, P.; Catinella, S.; Civelli, M.; Armani, E. Discovery and optimization of thiazolidinyl and pyrrolidinyl derivatives as Inhaled PDE4 inhibitors for respiratory diseases. J. Med. Chem. 2017, 60, 10026– 10046, DOI: 10.1021/acs.jmedchem.7b01044[ACS Full Text], [CAS], Google Scholar268https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvFWhs7rI&md5=44f2dc4fbac0d34580ff06d6cbca352dDiscovery and Optimization of Thiazolidinyl and Pyrrolidinyl Derivatives as Inhaled PDE4 Inhibitors for Respiratory DiseasesCarzaniga, Laura; Amari, Gabriele; Rizzi, Andrea; Capaldi, Carmelida; De Fanti, Renato; Ghidini, Eleonora; Villetti, Gino; Carnini, Chiara; Moretto, Nadia; Facchinetti, Fabrizio; Caruso, Paola; Marchini, Gessica; Battipaglia, Loredana; Patacchini, Riccardo; Cenacchi, Valentina; Volta, Roberta; Amadei, Francesco; Pappani, Alice; Capacchi, Silvia; Bagnacani, Valentina; Delcanale, Maurizio; Puccini, Paola; Catinella, Silvia; Civelli, Maurizio; Armani, ElisabettaJournal of Medicinal Chemistry (2017), 60 (24), 10026-10046CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Phosphodiesterase 4 (PDE4) is a key cAMP-metabolizing enzyme involved in the pathogenesis of inflammatory disease, and its pharmacol. inhibition has been shown to exert therapeutic efficacy in chronic obstructive pulmonary disease (COPD). Herein, the authors describe a drug discovery program aiming at the identification of novel classes of potent PDE4 inhibitors suitable for pulmonary administration. Starting from a previous series of benzoic acid esters, the authors explored the chem. space in the solvent-exposed region of the enzyme catalytic binding pocket. Extensive structural modifications led to the discovery of a no. of heterocycloalkyl esters as potent in vitro PDE4 inhibitors. (S*,S**)-18e (3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(((S)-1-((3-(dimethylcarbamoyl)phenyl)sulfonyl)pyrrolidine-2-carbonyl)oxy)ethyl)pyridine 1-oxide) and (S*,S**)-22e (3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((S)-3-(3-(dimethylcarbamoyl)phenylsulfonyl)thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide), in particular, exhibited optimal in vitro ADME and pharmacokinetics properties and dose-dependently counteracted acute lung eosinophilia in an exptl. animal model. The optimal biol. profile as well as the excellent solid-state properties suggest that both compds. have the potential to be effective topical agents for treating respiratory inflammatory diseases.
- 269Chen, T.; Reich, N. W.; Bell, N.; Finn, P. D.; Rodriguez, D.; Kohler, J.; Kozuka, K.; He, L.; Spencer, A. G.; Charmot, D.; Navre, M.; Carreras, C. W.; Koo-McCoy, S.; Tabora, J.; Caldwell, J. S.; Jacobs, J. W.; Lewis, J. G. Design of gut-restricted thiazolidine agonists of G protein-coupled bile acid receptor 1 (GPBAR1, TGR5). J. Med. Chem. 2018, 61, 7589– 7613, DOI: 10.1021/acs.jmedchem.8b00308[ACS Full Text], [CAS], Google Scholar269https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsFOksbjF&md5=d379f4ce804cfe94bb8543a88429a92fDesign of Gut-Restricted Thiazolidine Agonists of G Protein-Coupled Bile Acid Receptor 1 (GPBAR1, TGR5)Chen, Tao; Reich, Nicholas William; Bell, Noah; Finn, Patricia D.; Rodriguez, David; Kohler, Jill; Kozuka, Kenji; He, Limin; Spencer, Andrew G.; Charmot, Dominique; Navre, Marc; Carreras, Christopher W.; Koo-McCoy, Samantha; Tabora, Jocelyn; Caldwell, Jeremy S.; Jacobs, Jeffrey W.; Lewis, Jason GustafJournal of Medicinal Chemistry (2018), 61 (17), 7589-7613CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Bile acid signaling and metab. in the gastrointestinal tract have wide-ranging influences on systemic disease. G protein-coupled bile acid receptor 1 (GPBAR1, TGR5) is one of the major effectors in bile acid sensing, with demonstrated influence on metabolic, inflammatory and proliferative processes. The pharmacol. utility of TGR5 agonists has been limited by systemic target-related effects such as excessive gallbladder filling and blockade of gallbladder emptying. Gut-restricted TGR5 agonists, however, have the potential to avoid these side effects and consequently be developed into drugs with acceptable safety profiles. The authors describe the discovery and optimization of a series of gut-restricted TGR5 agonists that elicit a potent response in mice, with minimal gallbladder-related effects. The series includes 12 (4-(2,5-Dichloro-4-{[(4R)-4-[(4-cyclopropyl-1,2,3,4-tetrahydroquinoxalin-1-yl)carbonyl]-1,3-thiazolidin-3-yl]methyl}-phenoxymethyl)-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]-benzamide) (TGR5 EC50: human, 143 nM; mouse, 1.2 nM), a compd. with minimal systemic availability that may have therapeutic value to patients with type 2 diabetes mellitus, non-alc. steatohepatitis or inflammatory bowel disease.
- 270Tobias, P. S.; Kallen, R. G. Kinetics and equilibriums of the reaction of pyridoxal 5′-phosphate with ethylenediamine to form Schiff bases and cyclic geminal diamines. Evidence for kinetically competent geminal diamine intermediates in transimination sequences. J. Am. Chem. Soc. 1975, 97, 6530– 6539, DOI: 10.1021/ja00855a041[ACS Full Text], [CAS], Google Scholar270https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE2MXmtVGntbs%253D&md5=2b9636fc572d3dcd47785dd41ed119e2Kinetics and equilibriums of the reaction of pyridoxal 5'-phosphate with ethylenediamine to form Schiff bases and cyclic geminal diamines. Evidence for kinetically competent geminal diamine intermediates in transimination sequencesTobias, Peter S.; Kallen, Roland G.Journal of the American Chemical Society (1975), 97 (22), 6530-9CODEN: JACSAT; ISSN:0002-7863.Ethylenediamine and pyridoxal 5'-phosphate form Schiff bases and cyclic geminal diamines (imidazolidines) in aq. soln. in the pH range 7.5 to 14. The various pH-independent open chain cyclic tautomerization consts. and the microscopic proton dissociation consts. for the Schiff bases and cyclic geminal diamines were detd. from (1) the pH dependencies of electronic absorption spectra, (2) from the pH dependency of apparent assocn. consts. for addn. of ethylenediamine to pyridoxal 5'-phosphate and (3) model compds. The rates of the interconversion of the open chain Schiff bases and cyclic geminal diamines obtained from temp.-jump relaxation expts. appear to be hydronium ion catalyzed in the pH range 11.5 to 13 with kinetic consts. reaching values ∼105 sec-1 at the lower pH limit. This rate const. for a reaction which is in effect an intramol. transimination sequence is about 107 larger than the rate consts. for the alternative transimination route involving Schiff base hydrolysis and reformation and suggests that the transimination reactions in which the pyridoxal 5'-phosphate moiety is transferred from the ε-amino group of a lysine residue of an enzyme to be the α-amino group of a substrate amino acid at the active sites of pyridoxal 5'-phosphate dependent enzymes almost certainly involve enzyme bound geminal diamine intermediates and not enzyme bound pyridoxal 5'-phosphate itself. From a comparison of the rates of the intramol. transimination process and the turnover numbers of pyridoxal 5'-phosphate dependent enzymes, it appears that such enzymes may not need to catalyze the transimination process by contributions that are other than entropic in nature.
- 271Faine, S.; Harper, M. Independent antibiotic actions of hetacillin and ampicillin revealed by fast methods. Antimicrob. Agents Chemother. 1973, 3, 15– 18, DOI: 10.1128/AAC.3.1.15[Crossref], [PubMed], [CAS], Google Scholar271https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaE3sXhtlaht7k%253D&md5=41ab8d1c32bbf0f22b0f21390af1b7b8Independent antibiotic actions of hetacillin and ampicillin revealed by fast methodsFaine, S.; Harper, M.Antimicrobial Agents and Chemotherapy (1973), 3 (1), 15-18CODEN: AMACCQ; ISSN:0066-4804.In methods developed for the fast measurement of Escherichia coli or Staphylococcus aureus growth inhibition by hetacillin (I) [3511-16-8] or its hydrolysis product ampicillin [69-53-4], the rate of inhibition was a function of antibiotic concn. I had a half-life of 20 min at 37.deg. and pH 6.7, and was much less susceptible to penicillinase than was ampicillin. Thus, the use of high concns. of antibiotic in the presence of penicillinase permitted the demonstration of an independent antibiotic action of I.
- 272(a) Balkovec, J. M.; Hughes, D. L.; Masurekar, P. S.; Sable, C. A.; Schwartz, R. E.; Singh, S. B. Discovery and development of first in class antifungal caspofungin (CANCIDAS®) - a case study. Nat. Prod. Rep. 2014, 31, 15– 34, DOI: 10.1039/C3NP70070D[Crossref], [PubMed], [CAS], Google Scholar.272ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvVyqsr7E&md5=8064e3108df090056d00d50906c451afDiscovery and development of first in class antifungal caspofungin (CANCIDAS)-A case studyBalkovec, James M.; Hughes, David L.; Masurekar, Prakash S.; Sable, Carole A.; Schwartz, Robert E.; Singh, Sheo B.Natural Product Reports (2014), 31 (1), 15-34CODEN: NPRRDF; ISSN:0265-0568. (Royal Society of Chemistry)A review. This paper describes a fifteen year journey from concept to clin. discovery and development of the first in class caspofungin acetate (CANCIDAS) a parenteral antifungal agent. Caspofungin is a semisynthetic deriv. of pneumocandin B0, a naturally occurring, lipophilic cyclic peptide isolated from the fungus, Glarea lozoyensis. While the echinocandins had been previously studied for antifungal activity by several organizations, the class was dropped for a variety of reasons. Merck subsequently initiated a research program leading to the discovery and development of caspofungin. The multitude of challenges that ensued during the discovery and development process and which were successfully resolved by multi-disciplinary teams constitute the content of this article. The article consists of five sections that describe the discovery and development of caspofungin in chronol. order: (i) discovery of the natural product pneumocandin B0 from fungal fermns., (ii) fermn. development to improve the titer of pneumocandin B0 to make it com. viable, (iii) semisynthetic modification by medicinal chem. to successfully improve the properties of pneumocandin B0 leading to the discovery of caspofungin, (iv) development of com. semisynthesis and purifn. and formulation development to improve stability and (v) clin. development and approval of CANCIDAS as an antifungal drug which subsequently saved thousands of lives.(b) Bouffard, F. A.; Hammond, M. L.; Arison, B. H. Pneumocandin Bo acid degradate. Tetrahedron Lett. 1995, 36, 1405– 1408, DOI: 10.1016/0040-4039(95)00017-7[Crossref], [CAS], Google Scholar272bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXktF2ntro%253D&md5=6ea85d7cabb42e519e44ce6ca0282472Pneumocandin B0 acid degrateBouffard, F. Aileen; Hammond, Milton L.; Arison, Byron H.Tetrahedron Letters (1995), 36 (9), 1405-8CODEN: TELEAY; ISSN:0040-4039. (Elsevier)Acid-catalyzed ionization of pneumocandin B0 in a polar aprotic solvent produces the internally cyclized dehydration product I (R = 10, 12-dimethylmyristoyl).
- 273Kurtz, M. B.; Douglas, C.; Marrinan, J.; Nollstadt, K.; Onishi, J.; Dreikorn, S.; Milligan, J.; Mandala, S.; Thompson, J.; Balkovec, J. M. Increased antifungal activity of L-733,560, a water-soluble, semisynthetic pneumocandin, is due to enhanced inhibition of cell wall synthesis. Antimicrob. Agents Chemother. 1994, 38, 2750– 2757, DOI: 10.1128/AAC.38.12.2750[Crossref], [PubMed], [CAS], Google Scholar273https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXisVCrsLg%253D&md5=78d72afc2fd06295660f1ec1e60d094eIncreased antifungal activity of L-733,560, a water-soluble, semisynthetic pneumocandin, is due to enhanced inhibition of cell wall synthesisKurtz, M. B.; Douglas, C.; Marrinan, J.; Nollstadt, K.; Onishi, J.; Dreikorn, S.; Milligan, J.; Mandala, S.; Thompson, J.; et al.Antimicrobial Agents and Chemotherapy (1994), 38 (12), 2750-7CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)The pneumocandins are natural lipopeptide products of the echinocandin class which inhibit the synthesis of 1,3-β-D-glucan in susceptible fungi. The lack of a corresponding pathway in mammalian hosts makes this mode of action an attractive one for treating systemic infections. Substitution by an aminoethyl ether at the hemiaminal and dehydration and redn. of the glutamine of pneumocandin Bo produced a semisynthetic compd. (L-733,560) with intrinsic water soly., significantly increased potency, and a broader antifungal spectrum. To evaluate the mechanism for the improved antifungal efficacy, we detd. that L-733,560 was a more potent inhibitor of glucan synthase activity in vitro, did not affect the other membrane-bound enzymes tested, conferred susceptibility to lysis in the absence of osmotic support, and did not disrupt currents in liposomal bilayers or 86Rb+ fluxes from liposomes. In Aspergillus species L-733,560 also produced the same morphol. alterations as pneumocandin Bo. A stereoisomer of L-733,560 with poor antifungal activity was a weak inhibitor of glucan synthase. All of these results support the notion that the enhanced antifungal activity of L-733,560 is achieved by superior inhibition of glucan synthesis and not by nonspecific membrane effects or a second mode of action.
- 274(a) Bartizal, K.; Gill, C. J.; Abruzzo, G. K.; Flattery, A. M.; Kong, L.; Scott, P. M.; Smith, J. G.; Leighton, C. E.; Bouffard, A.; Dropinski, J. F.; Balkovec, J. In vitro preclinical evaluation studies with the echinocandin antifungal MK-0991 (L-743,872). Antimicrob. Agents Chemother. 1997, 41, 2326– 2332, DOI: 10.1128/AAC.41.11.2326[Crossref], [PubMed], [CAS], Google Scholar.274ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXntFKgu70%253D&md5=3f1763f897bef85dd48a6ef77ca18b37In vitro preclinical evaluation studies with the echinocandin antifungal MK-0991 (L-743,872)Bartizal, Ken; Gill, Charles J.; Abruzzo, George K.; Flattery, Amy M.; Kong, Li; Scott, Patricia M.; Smith, Jeffrey G.; Leighton, Claire E.; Bouffard, Aileen; Dropinski, James F.; Balkovec, JamesAntimicrobial Agents and Chemotherapy (1997), 41 (11), 2326-2332CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)The echinocandin MK-0991, formerly L-743,872, is a water-sol. lipopeptide that has been demonstrated in preclin. studies to have potent activity against Candida spp., Aspergillus fumigatus, and Pneumocystis carinii. An extensive in vitro biol. evaluation of MK-0991 was performed to better define the potential activities of this novel compd. Susceptibility testing with MK-0991 against approx. 200 clin. isolates of Candida, Cryptococcus neoformans, and Aspergillus isolates was conducted to det. MICs and min. fungicidal concns. MF(s). The MFC at which 90% of isolates are inhibited for 40 C. albicans clin. isolates was 0.5 μg/mL. Susceptibility testing with panels of antifungal agent-resistant species of Candida and C. neoformans isolates indicated that the MK-0991 MFCs for these isolates are comparable to those obtained for susceptible isolates. Growth kinetic studies of MK-0991 against Candida albicans and Candida tropicalis isolates showed that the compd. exhibited fungicidal activity (i.e., a 99% redn. in viability) within 3 to 7 h at concns. ranging from 0.06 to 1 μg/mL (0.25 to 4 times the MIC). Drug combination studies with MK-0991 plus amphotericin B found that this combination was not antagonistic against C. albicans, C. neoformans, or A. fumigatus in vitro. Studies with 0 to 50% pooled human or mouse serum established that fungal susceptibility to MK-0991 was not significantly influenced by the presence of human or mouse serum. Results from resistance induction studies suggested that the susceptibility for C. albicans was not altered by repeated exposure (40 passages) to MK-0991. Erythrocyte hemolysis studies with MK-0991 with washed and unwashed human or mouse erythrocytes indicated minimal hemolytic potential with this compd. These favorable results of preclin. studies support further studies with MK-0991 with humans.(b) Hajdu, R.; Thompson, R.; Sundelof, J. G.; Pelak, B. A.; Bouffard, F. A.; Dropinski, J. F.; Kropp, H. Preliminary animal pharmacokinetics of the parenteral antifungal agent MK-0991 (L-743,872). Antimicrob. Agents Chemother. 1997, 41, 2339– 2344, DOI: 10.1128/AAC.41.11.2339[Crossref], [PubMed], [CAS], Google Scholar274bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXntFKgu7k%253D&md5=b981d69499d0608b6c25270311384345Preliminary animal pharmacokinetics of the parenteral antifungal agent MK-0991 (L-743,872)Hajdu, Richard; Thompson, Randall; Sundelof, Jon G.; Pelak, Barbara A.; Bouffard, F. Aileen; Dropinski, James F.; Kropp, HelmutAntimicrobial Agents and Chemotherapy (1997), 41 (11), 2339-2344CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)MK-0991 (L-743,872) is a potent antifungal agent featuring long half-life pharmacokinetics. The pharmacokinetics of MK-0991 administered i.v. to mice, rats, rhesus monkeys, and chimpanzees is presented. Unique to MK-0991 is its consistent cross-species performance. The range of values for the pharmacokinetic parameters were as follows: clearance, 0.26 to 0.51 mL/min/kg; half-life, 5.2 to 7.6 h; and distributive vol., 0.11 to 0.27 L/kg. The level of protein binding of MK-0991 was detd. to be 96% in mouse and human serum. The compd. exhibited high affinities for human serum albumin and at least two lipid components. The rationale for the selection of MK-0991 as a drug development candidate was based on its two- to threefold superior pharmacokinetic performance in chimpanzees over the performance of an otherwise equiv. analog, L-733,560. Once-daily dosing for MK-0991 is indicated by a graphical comparison of levels in the circulations of chimpanzees and mice. In a study of the pharmacokinetics of MK-0991 in mouse tissue, the organs were assayed following i.p. administration. The area under the concn.-vs.-time curves (AUC) segregated the tissues into three exposure categories relative to plasma. The tissues with greater exposure than that for plasma were liver (16 times), kidney (3 times), and large intestine (2 times). The exposure for small intestine, lung, and spleen were equiv. to that for plasma. Organs with lower levels of exposure were the heart (0.3 times that for plasma), thigh (0.2 times), and brain (0.06 times). Kinetically, drug was cleared more slowly from all tissues than from plasma, indicating that terminal-phase equil. had not been achieved by 24 h. Thus, some measure of accumulation is predicted for all tissues. Single daily doses of MK-0991 should provide adequate systemic levels of fungicidal activity as a results of its long half-life pharmacokinetics, wide distribution, and slowly accumulating concns. in tissue.
- 275(a) Snyder, L. B.; Meng, Z.; Mate, R.; D’Andrea, S. V.; Marinier, A.; Quesnelle, C. A.; Gill, P.; DenBleyker, K. L.; Fung-Tomc, J. C.; Frosco, M.; Martel, A.; Barrett, J. F.; Bronson, J. J. Discovery of isoxazolinone antibacterial agents. Nitrogen as a replacement for the stereogenic center found in oxazolidinone antibacterials. Bioorg. Med. Chem. Lett. 2004, 14, 4735– 4739, DOI: 10.1016/j.bmcl.2004.06.076[Crossref], [PubMed], [CAS], Google Scholar.275ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXmvV2htL4%253D&md5=f54df1a32854d6244efacef632fb0e8cDiscovery of isoxazolinone antibacterial agents. Nitrogen as a replacement for the stereogenic center found in oxazolidinone antibacterialsSnyder, Lawrence B.; Meng, Zhaoxing; Mate, Robert; D'Andrea, Stanley V.; Marinier, Anne; Quesnelle, Claude A.; Gill, Patrice; DenBleyker, Kenneth L.; Fung-Tomc, Joan C.; Frosco, MaryBeth; Martel, Alain; Barrett, John F.; Bronson, Joanne J.Bioorganic & Medicinal Chemistry Letters (2004), 14 (18), 4735-4739CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A series of potential antimicrobial derivs. possessing bioisosteric replacements for the central oxazolidinone ring found in oxazolidinone antibacterials have been prepd. The design concept involved replacement of the requisite sp3-hybridized stereogenic center found at the 5-position of the oxazolidinone with a nitrogen atom. The synthesis and antibacterial activity of three such ring systems, the benzisoxazolinones, e.g., I, pyrroles, e.g., II, and isoxazolinones, e.g., III, is described.(b) Quesnelle, C. A.; Gill, P.; Roy, S.; Dodier, M.; Marinier, A.; Martel, A.; Snyder, L. B.; D’Andrea, S. V.; Bronson, J. J.; Frosco, M.; Beaulieu, D.; Warr, G. A.; DenBleyker, K. L.; Stickle, T. M.; Yang, H.; Chaniewski, S. E.; Ferraro, C. A.; Taylor, D.; Russell, J. W.; Santone, K. S.; Clarke, J.; Drain, R. L.; Knipe, J. O.; Mosure, K.; Barrett, J. F. Biaryl isoxazolinone antibacterial agents. Bioorg. Med. Chem. Lett. 2005, 15, 2728– 2733, DOI: 10.1016/j.bmcl.2005.04.003[Crossref], [PubMed], [CAS], Google Scholar275bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXks1Wjt7Y%253D&md5=1cff860acd12c136634ed19a5a39abbfBiaryl isoxazolinone antibacterial agentsQuesnelle, Claude A.; Gill, Patrice; Roy, Stephan; Dodier, Marco; Marinier, Anne; Martel, Alain; Snyder, Lawrence B.; D'Andrea, Stanley V.; Bronson, Joanne J.; Frosco, MaryBeth; Beaulieu, Danielle; Warr, Glen A.; DenBleyker, Ken L.; Stickle, Terry M.; Yang, Hyekyung; Chaniewski, Susan E.; Ferraro, Cheryl A.; Taylor, Dennis; Russell, John W.; Santone, Kenneth S.; Clarke, Junius; Drain, Rebecca L.; Knipe, Jay O.; Mosure, Kathleen; Barrett, John F.Bioorganic & Medicinal Chemistry Letters (2005), 15 (11), 2728-2733CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)In an era of increasing resistance to classical antibacterial agents, the synthetic oxazolidinone series of antibiotics has attracted much interest. Zyvox was the first oxazolidinone to be approved for clin. use against infections caused by multi-drug resistant Gram-pos. bacteria. In the course of studies directed toward the discovery of novel antibacterial agents, a new series of synthetic phenyl-isoxazolinone agents that displayed potent activity against Gram-pos. bacterial strains was recently discovered at Bristol-Myers Squibb. Extensive investigation of various substitutions on the Ph ring was then undertaken. We report here, the synthesis and antibacterial activity of a series of biaryl isoxazolinone compds. I (R = substituted Ph, 1-naphthyl, 2-pyridyl, 3-furyl, 4-tetrahydropyranyl, 4-pyridyl, etc.). Synthesis involved cross-coupling approaches.
- 276Kees, K. L.; Caggiano, T. J.; Steiner, K. E.; Fitzgerald, J. J., Jr.; Kates, M. J.; Christos, T. E.; Kulishoff, J. M., Jr.; Moore, R. D.; McCaleb, M. L. Studies on new acidic azoles as glucose-lowering agents in obese, diabetic db/db mice. J. Med. Chem. 1995, 38, 617– 628, DOI: 10.1021/jm00004a008[ACS Full Text], [CAS], Google Scholar276https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXjsFaisLs%253D&md5=967f2eb150cb5805338dc40b674d5683Studies on New Acidic Azoles as Glucose-Lowering Agents in Obese, Diabetic db/db MiceKees, Kenneth L.; Caggiano, Thomas J.; Steiner, Kurt E.; Fitzgerald, John J., Jr.; Kates, Michael J.; Christos, Thomas E.; Kulishoff, John M.; Moore, Robin D.; McCaleb, Michael L.Journal of Medicinal Chemistry (1995), 38 (4), 617-28CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Bioisosteric substitution was used as a tool to generate several new structural alternatives to the thiazolidine-2,4-dione and tetrazole heterocycles as potential antidiabetic agents. Among the initial leads that emerged from this strategy, a family of acidic azoles, isoxazol-3- and -5-ones and a pyrazol-3-one, showed significant plasma glucose-lowering activity (17-42% redn.) in genetically obese, diabetic db/db mice at a dose of 100 mg/kg/day ×4. Structure-activity relationship studies detd. that 5-alkyl-4-(arylmethyl)pyrazol-3-ones, which exist in soln. as arom. enol/iminol tautomers, were the most promising new class of potential antidiabetic agent (32-45% redn. at 20 mg/kg/d ×4). Included in this work are convenient syntheses for several types of acidic azoles that may find use as new acidic bioisosteres in medicinal chem. such as the antidiabetic lead 5-(trifluoromethyl)pyrazol-3-one, hydroxy tautomer, and aza homologs of the pyrazolones, 1,2,3-triazol-5-ones (hydroxy tautomer) and 1,2,3,4-tetrazol-5-one heterocycles. Log P and pKa data for 15 potential acidic bioisosteres, all appended to a 2-naphthalenylmethyl residue so as to maintain a similar distance between the acidic hydrogen and arene nucleus, are presented. This new data set allows comparison of a wide variety of potential acid mimetics (pKa 3.78-10.66; log P -0.21 to 2.76) for future drug design.
- 277(a) Noshi, T.; Kitano, M.; Taniguchi, K.; Yamamoto, A.; Omoto, S.; Baba, K.; Hashimoto, T.; Ishida, K.; Kushima, Y.; Hattori, K.; Kawai, M.; Yoshida, R.; Kobayashi, M.; Yoshinaga, T.; Sato, A.; Okamatsu, M.; Sakoda, Y.; Kida, H.; Shishido, T.; Naito, A. In vitro characterization of baloxavir acid, a first-in-class cap-dependent endonuclease inhibitor of the influenza virus polymerase PA subunit. Antiviral Res. 2018, 160, 109– 117, DOI: 10.1016/j.antiviral.2018.10.008[Crossref], [PubMed], [CAS], Google Scholar.277ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitVKhsbrL&md5=a7758d09b99a3b68221defe4c507838dIn vitro characterization of baloxavir acid, a first-in-class cap-dependent endonuclease inhibitor of the influenza virus polymerase PA subunitNoshi, Takeshi; Kitano, Mitsutaka; Taniguchi, Keiichi; Yamamoto, Atsuko; Omoto, Shinya; Baba, Keiko; Hashimoto, Takashi; Ishida, Kayo; Kushima, Yukihiro; Hattori, Kazunari; Kawai, Makoto; Yoshida, Ryu; Kobayashi, Masanori; Yoshinaga, Tomokazu; Sato, Akihiko; Okamatsu, Masatoshi; Sakoda, Yoshihiro; Kida, Hiroshi; Shishido, Takao; Naito, AkiraAntiviral Research (2018), 160 (), 109-117CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)Cap-dependent endonuclease (CEN) resides in the PA subunit of the influenza virus and mediates the crit. "cap-snatching" step of viral RNA transcription, which is considered to be a promising anti-influenza target. Here, we describe in vitro characterization of a novel CEN inhibitor, baloxavir acid (BXA), the active form of baloxavir marboxil (BXM). BXA inhibits viral RNA transcription via selective inhibition of CEN activity in enzymic assays, and inhibits viral replication in infected cells without cytotoxicity in cytopathic effect assays. The antiviral activity of BXA is also confirmed in yield redn. assays with seasonal type A and B viruses, including neuraminidase inhibitor-resistant strains. Furthermore, BXA shows broad potency against various subtypes of influenza A viruses (H1N2, H5N1, H5N2, H5N6, H7N9 and H9N2). Addnl., serial passages of the viruses in the presence of BXA result in isolation of PA/I38T variants with reduced BXA susceptibility. Phenotypic and genotypic analyses with reverse genetics demonstrate the mechanism of BXA action via CEN inhibition in infected cells. These results reveal the in vitro characteristics of BXA and support clin. use of BXM to treat influenza.(b) Miyagawa, M.; Akiyama, T.; Taoda, Y.; Takaya, K.; Takahashi-Kageyama, C.; Tomita, K.; Yasuo, K.; Hattori, K.; Shano, S.; Yoshida, R.; Shishido, T.; Yoshinaga, T.; Sato, A.; Kawai, M. Synthesis and SAR study of carbamoyl pyridone bicyclederivatives as potent inhibitors of influenza cap-dependent endonuclease. J. Med. Chem. 2019, 62, 8101– 8114, DOI: 10.1021/acs.jmedchem.9b00861[ACS Full Text], [CAS], Google Scholar277bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsFamsrrF&md5=73373f0232f87b3d5b685037612e8859Synthesis and SAR Study of Carbamoyl Pyridone Bicycle Derivatives as Potent Inhibitors of Influenza Cap-dependent EndonucleaseMiyagawa, Masayoshi; Akiyama, Toshiyuki; Taoda, Yoshiyuki; Takaya, Kenji; Takahashi-Kageyama, Chika; Tomita, Kenji; Yasuo, Kazuya; Hattori, Kazunari; Shano, Shinya; Yoshida, Ryu; Shishido, Takao; Yoshinaga, Tomokazu; Sato, Akihiko; Kawai, MakotoJournal of Medicinal Chemistry (2019), 62 (17), 8101-8114CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The medicinal chem. and structure-activity relationships (SAR) for a novel series of carbamoyl pyridone bicycle (CAB) compds. as influenza Cap-dependent endonuclease (CEN) inhibitors are disclosed. Substituent effects were evaluated at the C (N)-1, N-3, and C-7 positions of the CAB ring system using a docking study. Submicromolar EC50 values were achieved in the cellular assay with C-7-unsubstituted CAB which possessed a benzhydryl group on either the C-1 or the N-1 position. An N-3 substituent was found to be crit. for the plasma protein binding effect in vitro, and the CAB-N analog I exhibited reasonable total clearance (CLtot). More importantly, compd. I displayed significant efficacy in a mouse model infected with influenza viruses.
- 278Taoda, Y.; Miyagawa, M.; Akiyama, T.; Tomita, K.; Hasegawa, Y.; Yoshida, R.; Noshi, T.; Shishido, T.; Kawai, M. Dihydrodibenzothiepine: promising hydrophobic pharmacophore in the influenza cap-dependent endonuclease inhibitor. Bioorg. Med. Chem. Lett. 2020, 30, 127547, DOI: 10.1016/j.bmcl.2020.127547[Crossref], [PubMed], [CAS], Google Scholar278https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhvV2ntLzK&md5=5e935bf21cd2a6dfd9a8daf315111a84Dihydrodibenzothiepine: Promising hydrophobic pharmacophore in the influenza cap-dependent endonuclease inhibitorTaoda, Yoshiyuki; Miyagawa, Masayoshi; Akiyama, Toshiyuki; Tomita, Kenji; Hasegawa, Yasushi; Yoshida, Ryu; Noshi, Takeshi; Shishido, Takao; Kawai, MakotoBioorganic & Medicinal Chemistry Letters (2020), 30 (22), 127547CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)This work describes a set of discovery research studies of an influenza cap-dependent endonuclease (CEN) inhibitors with a carbamoyl pyridone bicycle (CAB) scaffold, particularly dibenzothiepine-substituted pyridotriazinediones such as I. Using influenza CEN inhibitory activity, antiviral activity and pharmacokinetic (PK) parameters as indexes, structure activity relationships (SAR) studies were performed at the N-1 and N-3 positions on the CAB scaffold, which is a unique template to bind two metals. The hydrophobic substituent at the N-1 position is extremely important for CEN inhibitory activity and antiviral activity, and dihydrodibenzothiepine was the most promising pharmacophore. I showed potent virus titer redn. over oseltamivir phosphate in an in vivo mouse model. I served as the lead compd. of baloxavir marboxil with a tricyclic scaffold, which was approved in Japan and the USA in 2018.
- 279(a) Heo, Y.-A. Baloxavir: first global approval. Drugs 2018, 78, 693– 697, DOI: 10.1007/s40265-018-0899-1[Crossref], [PubMed], [CAS], Google Scholar.279ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXnsVejsr0%253D&md5=1b11d92b5dc5807b6de1d1920ed1e4e5Baloxavir: First Global ApprovalHeo, Young-A.Drugs (2018), 78 (6), 693-697CODEN: DRUGAY; ISSN:0012-6667. (Springer International Publishing AG)Baloxavir marboxil (Xofluza; baloxavir) is an oral cap-dependent endonuclease inhibitor that has been developed by Roche and Shionogi. The drug blocks influenza virus proliferation by inhibiting the initiation of mRNA synthesis. In Feb. 2018, baloxavir received its first global approval in Japan for the treatment of influenza A or B virus infections. Phase III development is underway in the USA, EU and other countries for this indication. This article summarized the milestones in the development of baloxavir leading to this first global approval for influenza A or B virus infections.(b) Shirley, M. Baloxavir marboxil: a review in acute uncomplicated influenza. Drugs 2020, 80, 1109– 1118, DOI: 10.1007/s40265-020-01350-8[Crossref], [PubMed], [CAS], Google Scholar279bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtlWgurbK&md5=84f34ff0b87aea5756502ba18e010c26Baloxavir Marboxil: A Review in Acute Uncomplicated InfluenzaShirley, MattDrugs (2020), 80 (11), 1109-1118CODEN: DRUGAY; ISSN:0012-6667. (Springer International Publishing AG)A review. Abstr.: Baloxavir marboxil (Xofluza; hereafter referred to as baloxavir), the prodrug of baloxavir acid, is a first-in-class, small mol. inhibitor of the polymerase acidic (PA) protein subunit of the influenza virus polymerase complex. Baloxavir (after conversion to baloxavir acid) acts to block influenza virus replication by inhibiting the cap-dependent endonuclease activity of the PA protein. Taken orally as a single dose, baloxavir is approved in the USA for the treatment of acute uncomplicated influenza in patients ≥ 12 years of age who have been symptomatic for ≤ 48 h. Data from randomized, double-blind, placebo- and oseltamivir-controlled phase III trials have shown that baloxavir is efficacious in improving influenza symptoms both in otherwise healthy adolescents and adults and in those at high risk of influenza complications, displaying similar efficacy to that of oseltamivir. Furthermore, there is evidence that baloxavir can reduce influenza viral load more rapidly than oseltamivir. Baloxavir has activity against influenza A and B viruses (including strains resistant to neuraminidase inhibitors) and is well tolerated. Evidence of the emergence and likely human-to-human transmission of variant viruses with reduced susceptibility to baloxavir highlights the importance of monitoring and surveillance for changes in influenza virus drug susceptibility patterns. However, currently available evidence suggests that baloxavir, with the benefits of a single oral dose regimen, provides a useful alternative to neuraminidase inhibitors for the treatment of acute uncomplicated influenza in adolescents and adults.
- 280Raheem, I. T.; Walji, A. M.; Klein, D.; Sanders, J. M.; Powell, D. A.; Abeywickrema, P.; Barbe, G.; Bennet, A.; Clas, S.; Dubost, D.; Embrey, M.; Grobler, J.; Hafey, M. J.; Hartingh, T. J.; Hazuda, D. J.; Miller, M. D.; Moore, K. P.; Pajkovic, N.; Patel, S.; Rada, V.; Rearden, P.; Schreier, J. D.; Sisko, J.; Steele, T. G.; Truchon, J.; Wai, J.; Xu, M.; Coleman, P. J. Discovery of 2-pyridinone aminals: a prodrug strategy to advance a second generation of HIV-1 integrase strand transfer inhibitors. J. Med. Chem. 2015, 58, 8154– 8165, DOI: 10.1021/acs.jmedchem.5b01037[ACS Full Text], [CAS], Google Scholar280https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsFersrvJ&md5=bec0c2f7710a1e4e8cc3a502067a2236Discovery of 2-Pyridinone Aminals: A Prodrug Strategy to Advance a Second Generation of HIV-1 Integrase Strand Transfer InhibitorsRaheem, Izzat T.; Walji, Abbas M.; Klein, Daniel; Sanders, John M.; Powell, David A.; Abeywickrema, Pravien; Barbe, Guillaume; Bennet, Amrith; Childers, Karla; Christensen, Melodie; Clas, Sophie-Dorothee; Dubost, David; Embrey, Mark; Grobler, Jay; Hafey, Michael J.; Hartingh, Timothy J.; Hazuda, Daria J.; Kuethe, Jeffrey T.; Dunn, Jamie McCabe; Miller, Michael D.; Moore, Keith P.; Nolting, Andrew; Pajkovic, Natasa; Patel, Sangita; Peng, Zuihui; Rada, Vanessa; Rearden, Paul; Schreier, John D.; Sisko, John; Steele, Thomas G.; Truchon, Jean-Francois; Wai, John; Xu, Min; Coleman, Paul J.Journal of Medicinal Chemistry (2015), 58 (20), 8154-8165CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The search for new mol. constructs that resemble the crit. two-metal binding pharmacophore required for HIV integrase strand transfer inhibition represents a vibrant area of research within drug discovery. Here the authors present the discovery of a new class of HIV integrase strand transfer inhibitors based on the 2-pyridinone core of MK-0536. These efforts led to the identification of two lead compds. I and II with excellent antiviral activity and preclin. pharmacokinetic profiles to support a once-daily human dose prediction. Dose escalating PK studies in dog revealed significant issues with limited oral absorption and required an innovative prodrug strategy to enhance the high-dose plasma exposures of the parent mols.
- 281Reich, S. H.; Sprengeler, P. A.; Chiang, G. G.; Appleman, J. R.; Chen, J.; Clarine, J.; Eam, B.; Ernst, J. T.; Han, Q.; Goel, V. K.; Han, E.; Huang, V.; Hung, I.; Jemison, A.; Jessen, K. A.; Molter, J.; Murphy, D.; Neal, M.; Parker, G. S.; Shaghafi, M.; Sperry, S.; Staunton, J.; Stumpf, C. R.; Thompson, P. A.; Tran, C.; Webber, S. E.; Wegerski, C. J.; Zheng, H.; Webster, K. R. Structure-based design of pyridone-aminal eFT508 targeting dysregulated translation by selective mitogen-activated protein kinase interacting kinases 1 and 2 (MNK1/2) inhibition. J. Med. Chem. 2018, 61, 3516– 3540, DOI: 10.1021/acs.jmedchem.7b01795[ACS Full Text], [CAS], Google Scholar281https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXktlGhs7s%253D&md5=1254b674aa7e6d2037a06bc10e64e4daStructure-based Design of Pyridone-Aminal eFT508 Targeting Dysregulated Translation by Selective Mitogen-activated Protein Kinase Interacting Kinases 1 and 2 (MNK1/2) InhibitionReich, Siegfried H.; Sprengeler, Paul A.; Chiang, Gary G.; Appleman, James R.; Chen, Joan; Clarine, Jeff; Eam, Boreth; Ernst, Justin T.; Han, Qing; Goel, Vikas K.; Han, Edward Z. R.; Huang, Vera; Hung, Ivy N. J.; Jemison, Adrianna; Jessen, Katti A.; Molter, Jolene; Murphy, Douglas; Neal, Melissa; Parker, Gregory S.; Shaghafi, Michael; Sperry, Samuel; Staunton, Jocelyn; Stumpf, Craig R.; Thompson, Peggy A.; Tran, Chinh; Webber, Stephen E.; Wegerski, Christopher J.; Zheng, Hong; Webster, Kevin R.Journal of Medicinal Chemistry (2018), 61 (8), 3516-3540CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Dysregulated translation of mRNA plays a major role in tumorigenesis. Mitogen-activated protein kinase interacting kinases (MNK)1/2 are key regulators of mRNA translation integrating signals from oncogenic and immune signaling pathways through phosphorylation of eIF4E and other mRNA binding proteins. Modulation of these key effector proteins regulates mRNA, which controls tumor/stromal cell signaling. Compd. 23 (eFT508, 6'-((6-aminopyrimidin-4-yl)amino)-8'-methyl-2'H-spiro-[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione hydrochloride), an exquisitely selective, potent dual MNK1/2 inhibitor, was designed to assess the potential for control of oncogene signaling at the level of mRNA translation. The crystal structure-guided design leverages stereoelectronic interactions unique to MNK culminating in a novel pyridone-aminal structure described for the first time in the kinase literature. Compd. 23 has potent in vivo antitumor activity in models of diffuse large cell B-cell lymphoma and solid tumors, suggesting that controlling dysregulated translation has real therapeutic potential. Compd. 23 is currently being evaluated in Phase 2 clin. trials in solid tumors and lymphoma. Compd. 23 is the first highly selective dual MNK inhibitor targeting dysregulated translation being assessed clin.
- 282Paulini, R.; Laus Müller, K.; Diederich, F. Orthogonal multipolar interactions in structural chemistry and biology. Angew. Chem., Int. Ed. 2005, 44, 1788– 1805, DOI: 10.1002/anie.200462213[Crossref], [CAS], Google Scholar282https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXislWkt7s%253D&md5=6ad842547313b27fc1676e9c3a001909Orthogonal multipolar interactions in structural chemistry and biologyPaulini, Ralph; Mueller, Klaus; Diederich, FrancoisAngewandte Chemie, International Edition (2005), 44 (12), 1788-1805CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. The past few decades of mol. recognition studies have greatly enhanced our knowledge on apolar, ion-dipole, and hydrogen-bonding interactions. However, much less attention has been given to the role that multipolar interactions, in particular those with orthogonal dipolar alignment, play in organizing a crystal lattice or stabilizing complexes involving biol. receptors. By using results from database mining, this review attempts to give an overview of types and structural features of these previously rather overlooked interactions. A no. of illustrative examples of these interactions found in X-ray crystal structures of small mols. and protein-ligand complexes demonstrate their propensity and thus potential importance for both, chem. and biol. mol. recognition processes.
- 283A study to evaluate the efficacy and safety of TAK-906 in adult participants with symptomatic idiopathic or diabetic gastroparesis. https://clinicaltrials.gov/ct2/show/NCT03544229 (accessed April 29, 2021).
- 284Whiting, R. L.; Darpo, B.; Chen, C.; Fletcher, M.; Combs, D.; Xue, H.; Stoltz, R. R. Safety, pharmacokinetics, and pharmacodynamics of trazpiroben (TAK-906), a novel selective D2/D3 receptor antagonist: a Phase 1 randomized, placebo-controlled single- and multiple-dose escalation study in healthy participants. Clin. Pharmacol. Drug Dev. 2021, in press. DOI: 10.1002/cpdd.906 . Epub ahead of print. PMID: 33462988.
- 285A study to evaluate the safety and efficacy of NG101 in adult participants with symptomatic diabetic or idiopathic gastroparesis. https://clinicaltrials.gov/ct2/show/NCT04303195 (accessed April 29, 2021).
- 286Nishihara, M.; Ramsden, D.; Balani, S. K. Evaluation of the drug-drug interaction potential for trazpiroben (TAK-906), a D2/D3 receptor antagonist for gastroparesis, towards cytochrome P450s and transporters. Xenobiotica 2021 in press. 51 668 DOI: 10.1080/00498254.2021.1912438 .[Crossref], [PubMed], [CAS], Google Scholar286https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXptFyrsLo%253D&md5=83ebdee86cd6ffeafb8aceef24a89091Evaluation of the drug-drug interaction potential for trazpiroben (TAK-906), a D2/D3 receptor antagonist for gastroparesis, towards cytochrome P450s and transportersNishihara, Mitsuhiro; Ramsden, Diane; Balani, Suresh K.Xenobiotica (2021), 51 (6), 668-679CODEN: XENOBH; ISSN:0049-8254. (Taylor & Francis Ltd.)Trazpiroben (TAK-906), a peripherally selective dopamine D2/D3 receptor antagonist, is being developed for the treatment of patients with gastroparesis. The potential of trazpiroben to act as a perpetrator or a victim for cytochrome P 450 (CYP)- or transporter- mediated drug-drug interactions (DDIs) was evaluated following the latest regulatory guidelines. In vitro studies revealed that trazpiroben is metabolised mainly through a non-CYP pathway (56.7%) by multiple cytosolic, NADPH-dependent reductase, such as aldo-keto reductase and short-chain dehydrogenase/reductase including carbonyl reductases. Remaining metab. occurs through CYP3A4 and CYP2C8 (43.3%). Trazpiroben is neither an inhibitor nor an inducer of major CYP enzymes at a clin. relevant dose. It is a substrate of P-glycoprotein (P-gp) and org. anion transporting polypeptide (OATP) 1B1/1B3, but is not an inhibitor of transporters listed in the DDI guidelines at a clin. relevant dose. This is consistent with findings from CYP3A and P-gp-based clin. assessment showing no substantial change (≤2-fold) in trazpiroben exposure when co-administered with itraconazole. Collectively, trazpiroben has low potential of enzyme-mediated DDIs and is unlikely to act as a perpetrator of transporter-mediated DDIs but there may be a potential to act as a victim of OATP1B1/1B3 DDI that will be evaluated clin.
- 287(a) Bond, S.; Draffan, A. G.; Fenner, J. E.; Lambert, J.; Lim, C. Y.; Lin, B.; Luttick, A.; Mitchell, J. P.; Morton, C. J.; Nearn, R. H.; Sanford, V.; Stanislawski, P. C.; Tucker, S. P. The discovery of 1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-ones as a new class of respiratory syncytial virus (RSV) fusion inhibitors. Part 1. Bioorg. Med. Chem. Lett. 2015, 25, 969– 975, DOI: 10.1016/j.bmcl.2014.11.018[Crossref], [PubMed], [CAS], Google Scholar.287ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvFGis7rO&md5=3c21eca5a14547d10972c182d4c89c80The discovery of 1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-ones as a new class of respiratory syncytial virus (RSV) fusion inhibitors. Part 1Bond, Silas; Draffan, Alistair G.; Fenner, Jennifer E.; Lambert, John; Lim, Chin Yu; Lin, Bo; Luttick, Angela; Mitchell, Jeffrey P.; Morton, Craig J.; Nearn, Roland H.; Sanford, Vanessa; Stanislawski, Pauline C.; Tucker, Simon P.Bioorganic & Medicinal Chemistry Letters (2015), 25 (4), 969-975CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Respiratory syncytial virus (RSV) is a major cause of respiratory tract infections in infants, young children and adults. Compd. 1a (9b-(4-chlorophenyl)-1-(4-fluorobenzoyl)-1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-one) was identified as an inhibitor of A and B strains of RSV targeting the fusion glycoprotein. SAR was developed by systematic exploration of the Ph (R1) and benzoyl (R2) groups. Furthermore, introduction of a nitrogen at the 8-position of the tricyclic core resulted in active analogs with improved properties (aq. soly., protein binding and log D) and excellent rat pharmacokinetics (e.g., rat oral bioavailability of 89% for compd. 17, I).(b) Bond, S.; Draffan, A. G.; Fenner, J. E.; Lambert, J.; Lim, C. Y.; Lin, B.; Luttick, A.; Mitchell, J. P.; Morton, C. J.; Nearn, R. H.; Sanford, V.; Anderson, K. H.; Mayes, P. A.; Tucker, S. P. 1,2,3,9b-Tetrahydro-5H-imidazo[2,1-a]isoindol-5-ones as a new class of respiratory syncytial virus (RSV) fusion inhibitors. Part 2: Identification of BTA9881 as a preclinical candidate. Bioorg. Med. Chem. Lett. 2015, 25, 976– 981, DOI: 10.1016/j.bmcl.2014.11.024[Crossref], [PubMed], [CAS], Google Scholar287bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvFGis7rN&md5=6a0df66bad0f8c19627d2cf31bccca611,2,3,9b-Tetrahydro-5H-imidazo[2,1-a]isoindol-5-ones as a new class of respiratory syncytial virus (RSV) fusion inhibitors. Part 2: Identification of BTA9881 as a preclinical candidateBond, Silas; Draffan, Alistair G.; Fenner, Jennifer E.; Lambert, John; Lim, Chin Yu; Lin, Bo; Luttick, Angela; Mitchell, Jeffrey P.; Morton, Craig J.; Nearn, Roland H.; Sanford, Vanessa; Anderson, Kelly H.; Mayes, Penelope A.; Tucker, Simon P.Bioorganic & Medicinal Chemistry Letters (2015), 25 (4), 976-981CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Respiratory syncytial virus (RSV) is a major cause of respiratory tract infections in infants, young children and adults. 1,2,3,9b-Tetrahydro-5H-imidazo[2,1-a]isoindol-5-ones with general structure 1 were previously identified as promising inhibitors of RSV targeting the fusion glycoprotein. In particular, the introduction of a nitrogen at the 8-position of the tricyclic core yielded lead compds. Extensive exploration of the R2 group established that certain heterocyclic amides conferred potent RSV A&B activity and a good balance of physicochem. and pharmacokinetic properties. The antiviral activity was found to reside in a single enantiomer and BTA9881 (I) was identified as a candidate for preclin. development.
- 288Gentry, P. R.; Kokubo, M.; Bridges, T. M.; Kett, N. R.; Harp, J. M.; Cho, H. P.; Smith, E.; Chase, P.; Hodder, P. S.; Niswender, C. M.; Daniels, J. S.; Conn, P. J.; Wood, M. R.; Lindsley, C. M. Discovery of the first M5-selective and CNS penetrant negative allosteric modulator (NAM) of a muscarinic acetylcholine receptor: (S)-9b-(4-chlorophenyl)-1-(3,4-difluorobenzoyl)-2,3-dihydro-1H-imidazo[2,1-a]isoindol-5(9bH)-one (ML375). J. Med. Chem. 2013, 56, 9351– 9355, DOI: 10.1021/jm4013246[ACS Full Text], [CAS], Google Scholar288https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhs1ylsLzN&md5=fd5f4e5155d57ddb882bd68b0544be4eDiscovery of the First M5 Selective and CNS Penetrant Negative Allosteric Modulator (NAM) of a Muscarinic Acetylcholine Receptor: (S) 9b-(4-Chlorophenyl)-1-(3,4-difluorobenzoyl)-2,3-dihydro 1H imidazo[2,1a]isoindol-5(9bH)one (ML375)Gentry, Patrick R.; Kokubo, Masaya; Bridges, Thomas M.; Kett, Nathan R.; Harp, Joel M.; Cho, Hyekyung P.; Smith, Emery; Chase, Peter; Hodder, Peter S.; Niswender, Colleen M.; Daniels, J. Scott; Conn, P. Jeffrey; Wood, Michael R.; Lindsley, Craig W.Journal of Medicinal Chemistry (2013), 56 (22), 9351-9355CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A functional high throughput screen and subsequent multidimensional, iterative parallel synthesis effort identified the first muscarinic acetylcholine receptor (mAChR) neg. allosteric modulator (NAM) selective for the M5 subtype. ML375 is a highly selective M5 NAM with submicromolar potency (human M5 IC50 = 300 nM, rat M5 IC50 = 790 nM, M1-M4 IC50 > 30 μM), excellent multispecies PK, high CNS penetration, and enantiospecific inhibition.